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Activation of the arginine-nitric oxide pathway in primary sensory neurons contributes to dipyrone-induced spinal and peripheral analgesia
Abstract
The objective of this study was to investigate the site of action of dipyrone in rat paw prostaglandin-induced hyperalgesia. The intracerebroventricular (i.c.v.) injection of dipyrone had no effect on the hyperalgesic response to prostaglandins. In contrast, intraplantar (i.pl.) and intrathecal (i.t.) injections produced dose-dependent analgesic effects. The analgesia observed following the intraperitoneal (i.p.), i.t., i.pl. or combined i.t. and i.pl. administration of dipyrone was abolished by pretreating the paws with L-NMMA (a nitric oxide synthase inhibitor) or methylene blue (MB, an inhibitor of soluble guanylate cyclase). These results support the suggestion that dipyrone-mediated antinociception results from a combined spinal and peripheral effect in the primary peripheral sensory neuron via stimulation of the arginine/cGMP pathway.
... Supporting this idea, the peripheral analgesic effect of sodium nitroprusside was shown to be enhanced by intra-plantar injection of cGMP and phosphodiesterase inhibitors. It was also blocked by an sGC inhibitor, methylene blue [80][81][82][83][84][85]. Because ACh induces NO release from endothelial cells and activates the sGC signal, the participation of the NO-cGMP pathway in the peripheral analgesia promoted by ACh was tested. ...
... Our group examined the possible peripheral analgesic mechanisms of dipyrone. Lorenzetti and Ferreira initially showed that the local injection of dipyrone in rat paws inhibited carrageenan-induced inflammatory hyperalgesia, without anti-edematogenic effects; dipyrone, similarly to morphine, directly blocked ongoing hyperalgesia induced by PGE 2 and isoprenaline, suggesting a direct effect upon PSN excitability [81]. The role of the NO-cGMP pathway in the mechanisms of action of dipyrone was suggested because NOS and sGC inhibitors prevented dipyrone-mediated analgesia [83]; furthermore, a selective inhibitor of nNOS prevented dipyrone-mediated antinociception [136]; finally, the local antinociceptive effects of dipyrone were abolished by pre-treatment with NOS inhibitors [137]. ...
... The involvement of the NO pathway in the peripheral analgesic actions of other drugs and endogenous substances has also been extensively investigated. There is evidence that peripheral cannabinoids (a CB1-dependent effect), PPAR-γ agonists, xylazine, hormones such as estradiol and melatonin, bovine lactoferrin, choline (via alpha-7 nicotinic receptors), hydrogen sulfide releasing drugs, phosphodiesterase inhibitors, and pertussis toxin engage the NO-cGMP signaling to promote peripheral antinociception in various experimental models of inflammatory pain [81,83,137,138,[149][150][151][152][153][154][155][156][157][158]. In addition, not only did these analgesic drugs and endogenous substances elicit peripheral analgesia through the activation of the NO pathway, but there was also compelling evidence that alternative therapies such as electroacupuncture and natural products (e.g., plant extracts, venoms, and toxins) also required the integrity of this pathway to exert peripheral analgesia [152,[159][160][161][162][163][164][165]. ...
... A dipirona parece atuar exercendo bloqueio direto da hiperalgesia inflamatória por PGE 2 , supostamente promovendo dessensibilização dos nociceptores periféricos (Lorenzetti, Ferreira, 1985). Este mecanismo de dessensibilização, provavelmente envolve a ativação da via óxido-nítrico – GMPc no nociceptor (Duarte et al., 1992;Lorenzetti, Ferreira, 1996). A ação analgésica de diversos agentes, tais como a morfina, a nitroglicerina, o diclofenaco, a nimesulida, o meloxicam e o cetorolaco também parece depender da ativação endógena da via óxido-nítrico – GMPc para a dessensibilização do nociceptor (Ferreira et al., 1991;Ferreira et al., 1992;Tonussi, Ferreira, 1994;Islas-Caderra et al., 1999;Aguirre-Bañuelos, Granados-Soto, 2000;Lázaro-Ibáñez et al., 2001). ...
... instalação da analgesia de longa duração da dipirona (Dip: 114,0±14,0 g; Dip+L-NAME: 246,0±18,0 g; Dip+LNAME+L-Arg: 116,0±10,0 g) (Figura 2). Os fármacos foram administrados concomitantemente no 14° dia após a CNC, pela via intraplantar. A administração de L-Arg (500 mg pata-1 ) não alterou o desenvolvimento da hiperalgesia neuropática (Figura 2).Lorenzetti, Ferreira, 1996) e dipirona (80 mg pata-1 ), no 14° dia após a CNC (Figura 4), inibiu o desenvolvimento da analgesia de longa duração da dipirona, sendo observada redução significativa no 21° dia após a CNC (Sal: 220,0±30,0 g Dip+Cloreto de metiltionínio: 174,0±12,0 g e Dip: 56,0±14,0 g; P<0,05). Além disso, a administração concomitante de ODQ (50 mg p ...
... A administração de L-Arg (500 mg pata-1 ) não alterou o desenvolvimento da hiperalgesia neuropática (Figura 2).Lorenzetti, Ferreira, 1996) e dipirona (80 mg pata-1 ), no 14° dia após a CNC (Figura 4), inibiu o desenvolvimento da analgesia de longa duração da dipirona, sendo observada redução significativa no 21° dia após a CNC (Sal: 220,0±30,0 g Dip+Cloreto de metiltionínio: 174,0±12,0 g e Dip: 56,0±14,0 g; P<0,05). Além disso, a administração concomitante de ODQ (50 mg pata-1 ) (Lorenzetti, Ferreira, 1996) e dipirona (80 mg pata-1 ), no 14° dia após a CNC, também inibiu o desenvolvimento da analgesia de longa duração da dipirona (Figura 5), sendo observada redução significativa no 21° dia após a CNC (Sal: 254,0±18,0 g Dip+ODQ: 216,0±12,0 g e Dip: 120,0±11,0 g; P<0,05).Soares et al., 2000), no 14º dia após a CNC, induziu efeito analgésico significativo e de longa duração sobre a hiperalgesia mecânica neuropática, avaliado até o 28º dia após a CNC (Sal: 220,0±12,0 g; SNP: 110,0±10,0 g; P<0,05). ...
O efeito analgésico de longa duração da dipirona foi avaliado em um modelo de dor neuropática assim como a participação da via óxido nítrico-GMPc neste mecanismo analgésico. Uma única administração intraplantar de dipirona (80 µg), no 14º dia após a instalação da hiperalgesia neuropática induzida pela constrição do nervo ciático exerceu um efeito analgésico, significativo e de longa duração. A inibição da óxido nítrico sintetase com L-NAME (50 ou 100 µg/pata), ou do óxido nítrico (NO) endógeno com hemoglobina (10 ou 30 µg/pata), bloquearam o desenvolvimento do efeito analgésico da dipirona. A L-arginina (500 µg/pata) reverteu o efeito do L-NAME. Cloreto de metiltionínio (azul de metileno) (500 µg/pata), ODQ (50 µg/pata) (bloqueadores da guanilil ciclase) ou glibenclamida (100, 200 ou 300 µg/pata) (bloqueador de canais de K+ sensíveis ao ATP) inibiram o efeito analgésico da dipirona. O nitroprussiato de sódio administrado no 14º dia após a instalação da hiperalgesia neuropática também exerceu efeito analgésico de longa duração, semelhante ao observado com a dipirona. Sugerimos que a ação analgésica periférica e de longa duração da dipirona, neste modelo experimental, ocorra devido a provável dessensibilização dos nociceptores, envolvendo a via óxido nítrico - GMPc e canais de K+ sensíveis ao ATP.
... [43,44] . Há, ainda, evidências de ação central deste medicamento ocasionando assim inibição da transmissão do impulso na medula espinhal [45] . ...
... As diferenças nos resultados encontrados podem ser resultado da dosagem, via de administração, preparação da planta utilizada e sua composição fitoquímica. No presente estudo, a composição fitoquímica não foi analisada, não sendo possível avaliar as concentrações de compostos potencialmente analgésicos como o citral, o mirceno, os compostos polifenóis, os flavonoides e os taninos no OE utilizado, que poderiam contribuir para uma a atividade antinociceptiva, de acordo com estudos prévios [23,45,50] . ...
A dor é caracterizada como uma experiência sensorial e emocional desagradável associada a um dano ou lesão tecidual, sendo detectada por meio dos receptores especializados denominados nociceptores. A antinocicepção é o processo em que há a inibição da transmissão da informação nociceptiva, sendo mediada por sistemas endógenos e alcançada por substâncias exógenas, como os fármacos. A necessidade de se buscar novos compostos farmacológicos que auxiliam no tratamento da dor compõe um amplo campo de estudo, sendo assim, o presente trabalho objetivou testar um modelo biológico utilizando o peixe D. rerio para avaliação do potencial antinociceptivo de substâncias extraídas de plantas. Utilizou-se 24 peixes que foram filmados por 5 min (linha de base), tratados com veículo (Controle, n=8), óleo essencial de C. citratus (200 mg/kg, n=8) ou dipirona (100 mg/kg, n=8), após 30 minutos os animais foram submetidos ao teste nociceptivo da formalina e novamente filmados por 5 min (pós-estímulo), para avaliação comportamental. Foi observada diminuição da atividade locomotora em resposta à formalina, sendo este efeito bloqueado pelo tratamento com dipirona. O óleo essencial (OE) não apresentou efeitos significativos sobre a nocicepção, sendo necessários estudos complementares para a determinação de seu potencial antinociceptivo.
... It is still debated whether the site of action of dipyrone is in the peripheral or in the central nervous system. In the periphery, in addition to cyclooxygenase inhibition, the anti-hyperalgesic action of dipyrone has been associated with the activation of L-arginine-NO-cGMP pathway and the subsequent opening of K ATP channels [1,2]. Recent evidence suggests that cannabinoid CB 1 receptor activation also mediates the peripheral analgesic effect of dipyrone [3]. ...
... Activation of descending inhibitory pathways and contribution of endogenous opioid release are indicated to play role in its central analgesic effect [4][5][6][7][8]. Cyclooxygenase inhibition, L-arginine-NO-cGMP pathway and participation of the endogenous cannabinoid system are also among the proposed mechanism for its central antinociceptive action [1,[9][10][11]. Recently, we have also shown that nociceptin/ orphanin FQ receptors contribute to dipyroneinduced antinociception (unpublished data). The purpose of the present study was to examine whether neurotoxic destruction of descending serotonergic and noradrenergic pathways influence intraperitoneal dipyrone-induced antinociception and whether various spinal serotonergic receptor and adrenoceptor subtypes participate in this antinociception. ...
The antinociceptive effect of dipyrone is partly due to its action upon pain-related central nervous system structures. Despite intensive research, the precise mechanisms mediating its analgesic effects remain unclear. Here, we aimed to determine whether neurotoxic destruction of descending inhibitory pathways affect dipyrone-induced antinociception and whether various spinal serotonergic and adrenergic receptors are involved in this antinociception. The nociceptive response was assessed by the tail-flick test. Mice injected with dipyrone (150, 300, 600 mg/kg, i.p.) elicited dose-related antinociception. The neurotoxins 5,7-dihydroxytryptamine (50 μg/mouse) and 6-hydroxydopamine (20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. 3 days after neurotoxin injections, a significant reduction in the antinociceptive effect of dipyrone was observed. Intrathecal administration of monoaminergic antagonists (10 μg/mouse), the 5-HT2a antagonist ketanserin, the 5-HT3 antagonist ondansetron, the 5-HT7 antagonist SB-258719, α1-adrenoceptor antagonist prazosin, α2-adrenoceptor antagonist yohimbine, and the β-adrenoceptor antagonist propranolol also attenuated dipyrone antinociception. We propose that descending serotonergic and noradrenergic pathways play pivotal role in dipyrone-induced antinociception and spinal 5-HT2a, 5-HT3, and 5-HT7-serotonergic and α1, α2, and β-adrenergic receptors mediate this effect.
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... Lorenzetti and Ferreira (10) found that NO participates in dipyrone-mediated antinociception at the spinal level. These authors have demonstrated that intraplantar administration of L-NMMA abolished the antinociception produced by dipyrone (intraplantar) in rats (10). ...
... Lorenzetti and Ferreira (10) found that NO participates in dipyrone-mediated antinociception at the spinal level. These authors have demonstrated that intraplantar administration of L-NMMA abolished the antinociception produced by dipyrone (intraplantar) in rats (10). At the supraspinal level, Tesser-Viscaı´no et al. (11), in a model of temporomandibular joint arthritis, demonstrated that NO from nNOS spinal trigeminal neurons plays a role in antinociception. ...
Nitric oxide (NO) is a soluble gas that participates in important functions of the central nervous system, such as cognitive function, maintenance of synaptic plasticity for the control of sleep, appetite, body temperature, neurosecretion, and antinociception. Furthermore, during exercise large amounts of NO are released that contribute to maintaining body homeostasis. Besides NO production, physical exercise has been shown to induce antinociception. Thus, the present study aimed to investigate the central involvement of NO in exercise-induced antinociception. In both mechanical and thermal nociceptive tests, central [intrathecal (it) and intracerebroventricular (icv)] pretreatment with inhibitors of the NO/cGMP/KATP pathway (L-NOArg, ODQ, and glybenclamide) prevented the antinociceptive effect induced by aerobic exercise (AE). Furthermore, pretreatment (it, icv) with specific NO synthase inhibitors (L-NIO, aminoguanidine, and L-NPA) also prevented this effect. Supporting the hypothesis of the central involvement of NO in exercise-induced antinociception, nitrite levels in the cerebrospinal fluid increased immediately after AE. Therefore, the present study suggests that, during exercise, the NO released centrally induced antinociception.
... Accordingly, facilitation of endogenous opioidergic circuits and activation of descending paincontrol system, which inhibits pain transmission at the level of the spinal cord, are involved in this effect of dipyrone (3)(4)(5). Dipyrone is also proposed to be involved in interaction with the L-arginine-nitric oxide pathway, the glutamatergic system and the endogenous cannabinoid system, as well as its wellcharacterised effect of cyclooxygenase inhibition (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Here, we observed whether NOP receptors participate in dipyrone-induced anti-nociception. ...
... This effect is similar to that of paracetamol (16), whose hypothermic action has been studied more intensively than dipyrone. Paracetamol-induced hypothermia has been shown to be independent of the transient receptor vanilloid potential − 1 system and opioid, cannabinoid and NOP receptors (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). A cyclooxygenase-1 variant and its antioxidant and anti-glutamatergic properties are among the possible hypothermic mechanisms of paracetamol (29)(30)(31). ...
Dipyrone is one of the most commonly used non-opioid analgesic and antipyretic drug. Its anti-nociceptive and hypothermic effects have long been suspected to be centrally mediated. The involvement of the most recently discovered opioid peptide, nociceptin/orphanin FQ (N/OFQ), and its receptor (NOP) in pain transmission is controversial. It appears to be pro-nociceptive when administered supra-spinally, but exerts anti-nociceptive effects when injected spinally or systemically.
Investigation of the role of the N/OFQ system in paracetamol-induced anti-nociception and hypothermia led us to determine its role in the anti-nociceptive and hypothermic effects of dipyrone. Material and Methods Hot-plate and tail-flick tests were used to assess nociception, and a rectal thermometer was used to measure rectal temperature in mice.
Mice injected with dipyrone (150, 300, 600 mg/kg, i.p.) displayed dose-related anti-nociception and hypothermia. The NOP receptor antagonist JTC-801 (3 mg/kg, i.p.), at a dose that exerted no effect when used alone, alleviated dipyrone-induced anti-nociception but did not reverse dipyrone-induced hypothermia.
We conclude that NOP receptors participate in the anti-nociceptive, but not in the hypothermic, effects of dipyrone.
... In addition, other mechanisms underlying the analgesic effect of dipyrone have been described. Studies have associated the dipyrone anti-hyperalgesic effect with the activation of the L-arginine-NO-cGMP pathway and the subsequent opening of K ATP channel in peripheral tissue (Lorenzetti and Ferreira, 1996;Alves and Duarte, 2002). ...
... In addition, the analgesic doses of dipyrone are significantly lower than their anti-inflammatory doses (Coersmeier et al., 1986). The anti-hyperalgesic effect of dipyrone has been associated to the L-arginine-NO-cGMP pathway activation and the subsequent opening of K ATP channel in peripheral afferent nociceptor (Lorenzetti and Ferreira, 1996;Alves and Duarte, 2002). ...
Dipyrone (metamizole) is an analgesic pro-drug used to control moderate pain. It is metabolized in two major bioactive metabolites: 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA). The aim of this study was to investigate the participation of peripheral CB1 and CB2 cannabinoid receptors activation in the anti-hyperalgesic effect of dipyrone, 4-MAA or 4-AA. PGE2 (100ng/50µL/paw) was locally administered in the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test, before and 3hours after its injection. Dipyrone, 4-MAA or 4-AA was administered 30min before the von Frey test. The selective CB1 receptor antagonist AM251, CB2 receptor antagonist AM630, cGMP inhibitor ODQ or KATP channel blocker glibenclamide was administered 30min before dipyrone, 4-MAA or 4-AA. The antisense-ODN against CB1 receptor expression was intrathecally administered once a day during four consecutive days. PGE2-induced mechanical hyperalgesia was inhibited by dipyrone, 4-MAA, and 4-AA in a dose-response manner. AM251 or ODN anti-sense against neuronal CB1 receptor, but not AM630, reversed the anti-hyperalgesic effect mediated by 4-AA, but not by dipyrone or 4-MAA. On the other hand, the anti-hyperalgesic effect of dipyrone or 4-MAA was reversed by glibenclamide or ODQ. These results suggest that the activation of neuronal CB1, but not CB2 receptor, in peripheral tissue is involved in the anti-hyperalgesic effect of 4-aminoantipyrine. In addition, 4-methylaminoantipyrine mediates the anti-hyperalgesic effect by cGMP activation and KATP opening.
... A possible interference of dipyrone with the nociceptive activity of glutamate at the central level also has been suggested (Beirith et al., 1998). On the other hand, it has been reported that intrathecal and peripheral, but not intracerebroventricular, administration of dipyrone results in an antinociceptive effect on the hyperalgesic response to local prostaglandin injection, this effect being prevented by pretreatment with nitric oxide synthase or soluble guanylyl cyclase inhibitors (Lorenzetti & Ferreira, 1996). Therefore, it appears that the mechanism of action of the antinociceptive action of dipyrone has not yet been completely elucidated. ...
... Therefore, it appears that the mechanism of action of the antinociceptive action of dipyrone has not yet been completely elucidated. Antinocicep-tion seems to be the result of several peripheral and central mechanisms (Beirith et al., 1998;Granados-Soto et al., 1995;Laird et al., 1998;Lorenzetti & Ferreira, 1996). ...
The potentiation of the antinociceptive effect of morphine by dipyrone (metamizol) and the possible participation of a peripheral mechanism on such synergism were studied with the use of the formalin test in the rat. Nociception was induced by the intraplantar injection of diluted formalin (1%) in the right hind paw. Local administration of either dipyrone or morphine in the site of injury produced a dose-dependent antinociceptive effect. When combined, noneffective doses of morphine (1.25 μg/paw) and dipyrone (100 μg/paw) produced a significantly greater antinociceptive effect compared with either drug alone or saline. The opioid antagonist naloxone partly reversed the effect of the dipyrone–morphine combination. On the other hand, the inhibitor of nitric oxide (NO) synthesis, NG-L-nitro-arginine methylester (L-NAME), but not its inactive isomer, D-NAME, completely antagonized the effect of the dipyrone–morphine combination. These results suggest that the potentiation of morphine-induced antinociception by dipyrone in the formalin test requires an important participation of local release of NO, activating the NO–cyclic GMP pathway at the peripheral level.
... When administered intravenously, dipyrone also caused antinociception by activating endogenous opioid system (81). Other than its interaction with endogenous opioids, dipyrone is suggested to possess antinociceptive activity by classical COX inhibition (although weak) u n c o r r e c t e d p r o o f (82), and activation of the L-arginine-nitric oxide pathway and the subsequent K ATP channel opening (83), although there are some opposite findings (84, 85). In 2012, Rogosh et al. (29) demonstrated two unknown metabolites of dipyrone formed in the brain and spinal cord; FAAH seemed to be responsible for the formation of these metabolites, and once formed they bind weakly to cannabinoid receptors, but were modest inhibitors of COX-1 and -2. ...
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to produce antinociceptive effects mainly through peripheral COX-inhibition. Paracetamol and dipyrone are different from classical NSAIDs, because they exert weak anti-inflammatory activity; mechanisms other than peripheral COX inhibition appear to play role in their antinociceptive actions. In this review, we specified classical NSAIDs, paracetamol and dipyrone as "non-opioid analgesics" and discussed the mechanisms mediating participation of the endocannabinoid system in the antinociceptive effects of these analgesics. Non-opioid analgesics and their metabolites may activate cannabinoid receptors. In addition, several mechanisms are implicated in the elevation of endocannabinoid levels following administration of non-opioid analgesics. Of these, reduction of endocannabinoid degradation via FAAH and/or COX-2 inhibition, accumulation of arachidonic acid to endocannabinoid biosynthesis following COX inhibition, inhibition of cellular uptake of endocannabinoids directly or following inhibition of nitric oxide synthase production, and induction of endocannabinoid release are among the proposed mechanisms.
... Mechanistically, 15d-PGJ 2 activates PPAR-γ that induces the hyperpolarization of nociceptor neurons by activating the NO/cGMP/K + ATP channels signaling pathway through the release of β-endorphin 34,35 . In fact, activation of this signaling pathway is a mechanism by which morphine 36 , dypirone 37 , nitroxyl donor Angeli's salt 38 , and some flavonoids such as diosmin 39 and naringenin 40 produce analgesic effect. Thus, this mechanism contributes to the analgesic properties of 15d-PGJ 2 . ...
Gout arthritis (GA) is a painful inflammatory disease in response to monosodium urate (MSU) crystals in the joints. 15deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural activator of PPAR-γ with analgesic, anti-inflammatory, and pro-resolution properties. Thus, we aimed to evaluate the effect and mechanisms of action of 15d-PGJ2 nanocapsules (NC) in the model of GA in mice, since a reduction of 33-fold in the dose of 15d-PGJ2 has been reported. Mice were treated with 15d-PGJ2-loaded NC, inert NC, free 15d-PGJ2 (without NC), or 15d-PGJ2-loaded NC+ GW9662, a PPAR-γ inhibitor. We show that 15d-PGJ2-loaded NC provided analgesic effect in a dose that the free 15d-PGJ2 failed to inhibiting pain and inflammation. Hence, 15d-PGJ2-loaded NC reduced MSU-induced IL-1β, TNF-α, IL-6, IL-17, and IL-33 release and oxidative stress. Also, 15d-PGJ2-loaded NC decreased the maturation of IL-1β in LPS-primed BMDM triggered by MSU. Further, 15d-PGJ2-loaded NC decreased the expression of the components of the inflammasome Nlrp3, Asc, and Pro-caspase-1, as consequence of inhibiting NF-κB activation. All effects were PPAR-γ-sensitive. Therefore, we demonstrated that 15d-PGJ2-loaded NC present analgesic and anti-inflammatory properties in a PPAR-γ-dependent manner inhibiting IL-1β release and NF-κB activation in GA. Concluding, 15d-PGJ2-loaded NC ameliorates MSU-induced GA in a PPAR-γ-sensitive manner.
... We also investigated the role of the NO-cyclic GMP-K + channels pathway in the antinociceptive effect of (− )-epicatechin as this pathway has been reported to participate in the effect of several analgesic drugs (Duarte et al., 1990(Duarte et al., , 1992Tonussi and Ferreira, 1994;Granados-Soto et al., 1995;Lorenzetti and Ferreira, 1996;Granados-Soto et al., 1997;Nozaki-Taguchi and Yamamoto, 1998). In this respect, we found that L-NAME (a nonselective NOS inhibitor) (Rees et al., 1990), 7-NI (a selective nNOS inhibitor) (Moore et al., 1993), and ODQ (a NO-sensitive soluble guanylyl cyclase inhibitor) (Moro et al., 1996) prevented the antinociceptive effect of (− )-epicatechin in the formalin test. ...
The aim of this study was to investigate the antinociceptive potential of (-)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (-)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (-)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (-)-epicatechin was also prevented by the intraperitoneal administration of L-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K channel blocker), 4-aminopyridine (voltage-dependent K channel blocker), and iberiotoxin (large-conductance Ca-activated K channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (-)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.
... Inhibition of central cyclooxygenase system and activation of opioid and cannabinoid systems are important mechanism suggested for dipyrone, a strong analgesic and antipyretic agent [1][2][3]. Serotonergic-noradrenergic system, arginine-NO-cGMP pathway, neuronal potassium channels and inflammatory cytokine levels have been suggested as possible mechanisms for the analgesic action of dipyrone [4][5][6]. Other central effects, distinct from this analgesic effect, have been evaluated. ...
Purpose:
Antidepressant effects of analgesics have been investigate in both clinical and experimental studies. The purpose of this study was to investigate if the analgesic-antipyretic drug, dipyrone, also had antidepressant-like effects.
Methods:
Depression-like effects were investigated in an unpredictable chronic mild stress (UCMS) model in both male and female mice. Cage changes, light-dark cycle reversal, cage tilting, wet floor, empty cage, foreign material on the floor and predator sounds were used to induce light stress at different times for six weeks. Dipyrone was administered intraperitoneally beginning from the third week. Splash, rota-rod (RR) and forced swimming (FST) tests were performed at the seventh week as behavioural tests to evaluate the antidepressant-like effects of dipyrone. Coat state score (CSS) and weights of animals were recorded at seventh weeks. Results were analyzed using one or two-way ANOVA followed by the Bonferonni post hoc test.
Results:
Weight of UCMS-exposed mice did not change compared with controls; however, significant changes were observed in CSS in both sexes of stressed mice (p.
... Our present study managed to demonstrate the involvement of the cGMP pathway through the reversal of the anti-allodynic and antihyperalgesic activities of zerumbone using ODQ, a soluble guanylate cylcase inhibitor. Similar effects have been reported with analgesics such as dipyrone and diclofenac [56,57]. ...
The present study investigates the involvement of the L-Arginine-Nitric Oxide-cGMP-K+ ATP pathways responsible for the action of anti-Allodynic and antihyperalgesic activities of zerumbone in chronic constriction injury (CCI) induced neuropathic pain in mice. The role of L-Arginine-NO-cGMP-K+ was assessed by the von Frey and the Randall-Selitto tests. Both allodynia and hyperalgesia assessments were carried out on the 14th day post CCI, 30 min after treatments were given for each respective pathway. Anti-Allodynic and antihyperalgesic effects of zerumbone (10 mg/kg, i.p) were significantly reversed by the pre-Treatment of L-Arginine (10 mg/kg), 1H [1,2,4]Oxadiazole[4,3a]quinoxalin-1-one (ODQ), a soluble guanosyl cyclase blocker (2 mg/kg i.p.) and glibenclamide (ATP-sensitive potassium channel blocker) (10 mg/kg i.p.) (p < 0.05). Taken together, these results indicate that systemic administration of zerumbone produces significant anti-Allodynic and antihyperalgesic activities in neuropathic pain in mice possibly due to involvement of the L-Arginine-NO-cGMP-PKG-K+ ATP channel pathways in CCI model.
... It has been shown that at doses lower than 30 mg/kg, as in the herein described experiments, gabapentin acts only at the peripheral level [51]. Its antinociceptive effects [52] are supposed to be related to the peripheral release of nitric oxide (NO), a mediator shown to induce analgesia at this level [53,54]. Consequently, one possible mechanism to explain the observed synergy could be related to the peripheral MORs stimulation by PL265-protected-ENKs potentiated by the activation of NO/cGMP/K + ATP cascade [29,54,55]. ...
Background:
The first line pharmacological treatment of cancer pain is morphine and surrogates but a significant pain relief and a reduction of the side-effects of these compounds makes it necessary to combine them with other drugs acting on different targets. The aim of this study was to measure the antinociceptive effect on cancer-induced bone pain resulting from the association of the endogenous opioids enkephalin and non-opioid analgesic drugs. For this purpose, PL265 a new orally active single dual inhibitor of the two degrading enkephalins enzymes, neprilysin (NEP) and aminopeptidase N (APN) was used. It strictly increased the levels of enkephalin at their sites of releases. The selected non-opioid compounds are: gabapentin, A-317491 (P2X3 receptor antagonist), ACEA (CB1 receptor antagonist), AM1241 (CB2 receptor antagonist), JWH-133 (CB2 receptor antagonist), URB937 (FAAH inhibitor), and NAV26 (Nav1.7 channel blocker).
Methods:
Experiments. Experiments were performed in 5-6 weeks old (26-33g weight) C57BL/6 mice. Cell culture and cell inoculation. B16-F10 melanoma cells were cultured and when preconfluent, treated and detached. Finally related cells were resuspended to obtain a concentration of 2×106 cells/100μL. Then 105 cells were injected into the right tibial medullar cavity. Control mice were treated by killed cells by freezing. Behavioural studies. Thermal withdrawal latencies were measured on a unilatered hot plate (UHP) maintained at 49±0.2°C. Mechanical threshold values were obtained by performing the von Frey test using the "up and down" method. To evaluate the nature (additive or synergistic) of the interactions between PL265 and different drugs, an isobolographic analysis following the method described by Tallarida was performed.
Results:
The results demonstrate the ability of PL265, a DENKI that prevents the degradation of endogenous ENKs, to counteract cancer-induced bone thermal hyperalgesia in mice, by exclusively stimulating peripheral opioid receptors as demonstrated by used of an opioid antagonist unable to enter the brain. The development of such DENKIs, endowed with druggable pharmacokinetic characteristics, such as good absorption by oral route, can be considered as an important step in the development of much needed novel antihyperalgesic drugs. Furthermore, all the tested combinations resulted in synergistic antihyperalgesic effects. As shown here, the greatest synergistic antinociceptive effect (doses could be lowered by 70%) was produced by the combination of PL265 with the P2X3 receptor antagonist (A-317491), cannabinoid CB1 receptor agonist (exogenous, ACEA and endogenous URB937-protected-AEA) and Nav1.7 blocker (NAV26) whose mechanism of action involves the direct activation of the enkephalinergic system.
Conclusions:
These multi-target-based antinociceptive strategies using combinations of non-opioid drugs with dual inhibitors of enkephalin degrading enzymes may bring therapeutic advantages in terms of efficacy and safety by allowing the reduction of doses of one of the compounds or of both, which is of the utmost interest in the chronic treatment of cancer pain.
Implications:
This article presents synergistic antinociceptive effect produced by the combination of PL265 with non-opioid analgesic drugs acting via unrelated mechanisms. These multi-target-based antinociceptive strategies may bring therapeutic advantages by allowing the reduction of doses, which is of great interest in the chronic treatment of cancer pain.
... Obwohl der Wirkmechansimus von Metamizol nicht bis ins Detail geklärt ist, scheint es sich bei diesem Wirkstoff vorwiegend um einen im ZNS wirk samen Prostaglandinsynthesehemmer zu handeln. Des Weiteren werden opioiderge Wirkmechanismen, eine Wirkung auf die Signalkaskade des L-Arginin/NO/cGMP/K + -Kanals sowie Interaktionen mit dem Glutamatsystem diskutiert (2,3,5,24,33). Da die periphere Prostaglandinsynthese nur wenig gehemmt wird, fehlen Metamizol die für die "klassischen" NSAIDs charakteristischen antiphlogistischen Wirkungen. ...
Zusammenfassung
Unzureichend behandelte Schmerzen führen zu negativen systemischen Effekten und unter Umständen zu einer massiven Störung des Allgemeinbefindens unserer Patienten. Aus diesem Grund sollte ein Schmerzbeurteilungsplan standardmäßig in die klinischen Abläufe eingebunden sein. Für Hund und Katze stehen validierte Schmerz - beurteilungspläne zur Verfügung. Im Rahmen einer fortschrittlichen Schmerztherapie ist das Prinzip der multimodalen Analgesie zu beachten. Dies bedeutet, dass verschiedene analgetische Wirkstoffgruppen miteinander kombiniert werden, die ihre Wirkung an unterschiedlichen Stellen des Schmerzentstehungs- und Schmerzleitungssystems entfalten. Neben Opioiden, nichtsteroidalen Antiphlogistika und Lo - kalanästhetika finden unter anderem α2-Rezeptor-Agonisten, Ketamin und Gabapentin Anwendung. Hinzu kommen diverse nichtpharmakologische Therapieformen.
... Their mechanisms of actions are based on the inhibition of cyclooxygenase activity and, therefore, decreased prostaglandin synthesis. However, some studies have shown that they can produce antinociception through other mechanisms, such as the desensitization of nociceptors associated with the activation of the l-arginine/NO/cGMP pathway [21][22][23][24], the opening of ATPsensitive K + channels [25,26] and interactions with the opioid system [12][13][14][15][16][17][18][19]. ...
... A second strategy to control inflammatory pain is through the use of drugs, which are able to directly block ongoing nociceptor sensitization through peripheral actions (Lorenzetti and Ferreira 1985;Ferreira et al. 1991;Duarte et al. 1992). In fact, local administration of opioids and dipyrone reversed already established hyperalgesia induced by prostaglandin E 2 (PGE 2 ) (Ferreira 1972;Lorenzetti and Ferreira 1996). Therefore, in contrast to NSAIDs, drugs that act through the prevention of nociceptor sensitization by inhibiting prostaglandin synthesis are able to reverse ongoing inflammatory hyperalgesia. ...
The development of nitric oxide (NO)- and hydrogen sulfide (H2S)-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) has generated more potent anti-inflammatory drugs with increased safety profiles. A new hybrid molecule incorporating both NO and H2S donors into aspirin (NOSH-aspirin) was recently developed. In the present study, the antinociceptive activity of this novel molecule was compared with aspirin in different models of inflammatory pain. It was found that NOSH-aspirin inhibits acetic acid-induced writhing response and carrageenan (Cg)-induced inflammatory hyperalgesia in a dose-dependent (5–150 μmol/kg, v.o.) manner, which was superior to the effect of the same doses of aspirin. NOSH-aspirin's antinociceptive effect was also greater and longer compared to aspirin upon complete Freund's adjuvant (CFA)-induced inflammatory hyperalgesia. Mechanistically, NOSH-aspirin, but not aspirin, was able to reduce the production/release of interleukin-1 beta (IL-1β) during Cg-induced paw inflammation. Furthermore, NOSH-aspirin, but not aspirin, reduced prostaglandin E2-induced hyperalgesia, which was prevented by treatment with a ATP-sensitive potassium channel (KATP) blocker (glibenclamide; glib.). Noteworthy, the antinociceptive effect of NOSH-aspirin was not associated with motor impairment. The present results indicate that NOSH-aspirin seems to present greater potency than aspirin to reduce inflammatory pain in several models. The enhanced effects of NOSH-aspirin seems to be due to its ability to reduce the production of pronociceptive cytokines such as IL-1 β and directly block hyperalgesia caused by a directly acting hyperalgesic mediator in a mechanism dependent on modulation of KATP channels. In conclusion, we would like to suggest that NOSH-aspirin represents a prototype of a new class of analgesic drugs with more potent effects than the traditional NSAID, aspirin.
... However, the profiles of the analgesic activities of dipyrone and diclofenac differ from those of other common NSAIDs due to their direct antagonistic effects on PGE 2 -induced hyperalgesia. Hence, different mechanisms of action for the antagonistic effects have emerged, such as the dipyrone-and diclofenac-induced desensitization of nociceptors that are related to the activation of the L-arginine/NO/cGMP pathway [6,7,18,38]. Later studies have suggested that the diclofenac-induced peripheral antinociceptive effects are associated with the opening of ATP-sensitive K + channels [2,25]. ...
... Dipyrone failed to reduce PG levels in rat tissues and, accordingly, dipyrone gastrointestinal toxicity is negligible (Weithmann and Alpermann, 1985;Brogden, 1986;Sanchez et al., 2002;Berenguer et al., 2004). Thus, the pharmacological actions of PDs do not replicate the COXdependent effects of NSAIDs/coxibs and additional mechanisms (Lorenzetti and Ferreira, 1996;Sachs et al., 2004) have not received further support. ...
Although still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine, remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect.
Calcium responses and currents were studied in cultured, TRPA1-expressing rodent dorsal root ganglion neurons and human cells. Acute nociception and mechanical hypersensitivity were investigated in naïve and genetically manipulated mice.
Pyrazolone and PDs selectively inhibit calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2 O2 ). In line with recent results obtained with TRPA1 antagonists or TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuate TRPA1-mediated nociception and mechanical allodynia in models of inflammatory and neuropathic pain (formalin, carrageenan, partial sciatic nerve ligation, and the chemotherapeutic drug, bortezomib). Notably, dipyrone and propyphenazone attenuate carrageenan-evoked mechanical allodynia, without affecting prostaglandin E2 levels. PD main metabolites do not target TRPA1 and do not affect TRPA1-dependent nociception and allodynia.
Evidence that in rodents the nociceptive/hyperalgesic effect produced by TRPA1 activation is blocked by PDs suggests that a similar pathway is attenuated by PDs in humans, and that TRPA1 antagonists could be novel analgesics, devoid of the hematologic liability of PDs.
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... 21 In the present study, dipyrone and CB 1 receptor agonist treatment increased the latency response in a hotplate test, indicating an analgesic effect of dipyrone. 22 The analgesic properties of the endocannabinoid system have also been demonstrated for other drugs used extensively for the treatment of pain, such as paracetamol, ibuprofen and indomethacin. 9,23-25 The CB 1 receptor seems to be involved in analgesic effects and other responses, possibly by inhibiting the activity of adenylate cyclase. ...
Dipyrone is a non-steroidal anti-inflammatory drug (NSAID) used primarily as an analgesic and antipyretic. Some hypothesize that dipyrone activity can modulate other pathways, including endocannabinoid signaling. Thus, the aim of this study was to evaluate the possible role of endocannabinoids in mediating dipyrone activity. This study will be based on the tetrad effects of cannabinoids, which are an antinoceptive and cataleptic state, hypolocomotion, and hypothermia. Dipyrone treatment caused a decrease in locomotor activity, increased the latency to a thermal analgesic response, and induced a cataleptic and hypothermic state. These reactions are similar to the tetrad effects caused by the cannabinoid agonist, WIN 55,212-2. CB1 receptor antagonist reversed dipyrone's effects on locomotor activity, the cataleptic response and thermal analgesia. CB1 and TRPV1 antagonists accentuated the reduction in body temperature caused by dipyrone. However, CB2 antagonists did not alter the dipyrone-stimulated hypothermia response. These results indicate involvement of the endocannabinoid system, especially the CB1 receptor, in analgesia and the cataleptic effect and hypolocomotion. However, CB and TRPV1 receptors were not involved in hyporthermic effects. We hypothesize that dipyrone's mechanism of action may involve COX and FAAH inhibition, which together provide additional arachidonic acid as substrate for endocannabinoid synthesis or other related molecules. This increase in endocannabinoid availability enhances CB1 receptor stimulation, contributing to the observed effects. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... En este caso se cambió erróneamente la PCA, todos tenemos claros los efectos de la morfina epidural pero no así los del metamizol por dicha vía, de ahí que nos decidamos a comunicarlo. En la revisión de la bibliografía no encontramos ninguna referencia al respecto, aunque nos parece interesante destacar los estudios de investigación y farmacológicos, hechos en ratas y ratones sobre la administración intratecal de dipirona y su posible efecto analgésico central a través de su unión a receptores espinales o de modu-lación de vías de activación espinal; en alguno de estos estudios los análisis anatomopatológicos e histológicos no mostraron alteraciones estructurales en el tejido nervioso (4)(5)(6)(7). ...
The erroneous or accidental epidural administration of substances entails a potential morbidity (1,2) and mortality risk. Once the accident has happened, there is no effective treatment; therefore, prevention and measures aimed to avoid this type of errors are the best and most effective treat-ment. We present the case of a patient to which an infu-sion of morphine and metamizol was epidurally adminis-tered during approximately 4 hours in PCA programmed for intravenous administration. © 2004 Sociedad Española del Dolor. Published by Arán Ediciones, S.L.
... Thus, although ROCK-NO interactions have been demonstrated, the mechanisms underlying these interactions are not completely understood. The NO/ cGMP/PKG pathway is an important component of the peripheral analgesic effects associated with a range of known analgesic compounds (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Despite the well-documented analgesic or, more properly, antinociceptive effects related to this cGMP pathway, nociceptive as well as antinociceptive responses have been observed following injections of NO donors, cGMP analogues or L-arginine, depending on the dose and agent used (40)(41)(42)(43)(44)(45). ...
Rho-kinases (ROCKs), a family of small GTP-dependent enzymes, are involved in a range of pain models, and their inhibition typically leads to antinociceptive effects.
OBJECTIVES: To study the effects of inhibiting ROCKs using two known inhibitors, Y27632 and HA1077 (fasudil), administered locally, on nociception and paw edema in rats.
METHODS: A range of doses of Y27632 or HA1077 (2.5 μg to 1000 μg) were injected locally into rat paws alone or in combination with carrageenan, a known proinflammatory stimulus. Nociceptive responses to mechanical stimuli and increased paw volume, reflecting edema formation, were measured at 2 h and 3 h, using a Randall-Selitto apparatus and a hydroplethysmometer, respectively.
RESULTS: Animals treated with either ROCK inhibitor showed biphasic nociceptive effects, with lower doses being associated with pronociceptive, and higher doses with antinociceptive responses. In contrast, a monophasic dose-dependent increase in edema was observed in the same animals. Local injection of 8-bromo-cyclic (c)GMP, an activator of the nitric oxide/cGMP/protein kinase G pathway, also produced biphasic effects on nociceptive responses in rat paws; however, low doses were antinociceptive and high doses were pronociceptive. Local administration of cytochalasin B, an inhibitor of actin polymerization and a downstream mediator of ROCK activity, reversed the antinociceptive effect of Y27632.
CONCLUSIONS: The results of the present study suggest that ROCKs participate in the local mechanisms associated with nociception/antinociception and inflammation, with a possible involvement of the nitric oxide/cGMP/protein kinase G pathway. Also, drug effects following local administration may differ markedly from the effects following systemic administration. Finally, separate treatment of pain and edema may be needed to maximize clinical benefit in inflammatory pain.
... In this study, several mechanisms of action were analyzed for the TDC. In the present study, the antinociceptive effect of the TDC was prevented by L-NAME [Gibson et al., 1990] and ODQ [Moro et al., 1996], indicating a role for the NO-cyclic guanosine monophosphate (cGMP) pathway at the peripheral level in the formalin test, consistent with previous findings [Lorenzetti and Ferreira, 1996;Granados-Soto et al., 1997;Islas-Cadena et al., 1999;Sachs et al., 2004;Brito et al., 2006;Hernández-Pacheco et al., 2008]. Likewise, local peripheral administration of glibenclamide, an ATP-sensitive K + channel blocker [Edwards and Weston, 1993;Mixcoatl-Zecuatl et al., 2006;Hernández-Pacheco et al., 2008], also prevented the antinociceptive effect of the TDC. ...
Preclinical Research
Systemic coadministration of tramadol and dexketoprofen can produce antinociceptive synergism in animals. There has been only limited evaluation of this drug combination in the peripheral nervous system in terms of the antinociceptive interaction and its mechanisms. The aim of the present study was to evaluate the peripheral antinociceptive interaction between tramadol and dexketoprofen in the formalin test and the involvement of the nitric oxide ( NO )–cyclic guanosine monophosphate pathway and ATP ‐sensitive K ⁺ channels. Different doses of tramadol or dexketoprofen were administered locally to the formalin‐injured mouse paw and the antinociceptive effect evaluated. ED 50 values were calculated for both drugs alone and in combination. Coadministration of tramadol and dexketoprofen produced an antinociceptive synergistic interaction during the second phase of the formalin test. Pretreatment with NO antagonists, including l ‐ NG ‐nitroarginine methyl ester and 1 H ‐[1,2,4]‐oxadiazolo‐[4,3‐a]‐quinoxalin‐1‐one, or the ATP ‐sensitive K ⁺ channel antagonist glibenclamide reversed the antinociceptive synergistic effect of the tramadol–dexketoprofen combination, suggesting that NO and ATP ‐sensitive K ⁺ channels were involved.
... The inhibition of hyperalgesia was also seen with the positive control, dipyrone. One of the proposed mechanisms for dipyrone is in the activation of arginine-NO-cGMP-channel ATP-sensitive K + , which induces the desensitization of peripheral nociceptors [53]. ...
This study aimed at synthesizing the carvacrol propionate (CP) and evaluating its pharmacological profile. CP was obtained from carvacrol and propionyl chloride through an esterification reaction. Male Swiss mice were treated with CP (25, 50, or 100 mg/kg). We evaluated the analgesic effect, mechanical hyperalgesia, and anti-inflammatory effect. Pre-treatment with CP inhibited (p < 0.01 and 0.001) the formalin-induced nociception in both phases. CP inhibited (p < 0.05, 0.01, and 0.001) the development of mechanical hyperalgesia. CP was able to decrease the leukocyte recruitment (p < 0.001) and the amount of TNF-α (p < 0.001), IL-1β (p < 0.05), and protein leakage (p < 0.01) into the pleural cavity. In addition, the paw edema was inhibited by CP (p < 0.05, 0.01, and 0.001). The CP attenuates nociception, mechanical hyperalgesia, and inflammation, through an inhibition of cytokines.
... Many studies have demonstrated participation of the nitrergic system in nociceptive transmission (Riedel and Neeck, 2001) and its role in the antinociceptive effects (Brito et al., 2006;Lorenzetti and Ferreira, 1996). The pre-administration of L-NAME, an inhibitor of nitric oxide synthase enzyme (NOS), reversed only the antinociceptive effect of MAN suggesting the participation of L-arginine-nitric oxide-cGMP pathway. ...
... Data suggest that activation of the NO–cyclic GMP pathway plays an important role in mangiferin-induced antinociception at peripheral level in the formalin test. Our results are agree with several studies showing that local peripheral NO and cyclic GMP are important for the antinociceptive activity of several drugs (Lorenzetti and Ferreira, 1996; Granados-Soto et al., 1997; IslasCadena et al., 1999; Sachs et al., 2004; Brito et al., 2006; Hernandez-Pacheco et al., 2008 ). Likewise, local peripheral administration of glibenclamide, an ATP-sensitive K þ channel blocker (Edwards and Weston, 1993; Mixcoatl-Zecuatl et al., 2006; Hernandez-Pacheco et al., 2008 ), also prevented the antinociceptive effect of mangiferin. ...
... Among these, cyclooxygenase inhibition is surely well characterized elsewhere (Campos et al. 1999). Interactions with the l-arginine-nitric oxide pathway and/or the glutamatergic system are also suggested (Beirith et al. 1998;Hernandez-Delgadillo and Cruz 2006;Lorenzetti and Ferreira 1996;Siebel et al. 2004), although there are a few adverse opinions (Yilmaz and Ulugol 2009). ...
Cannabinoid CB1 receptors have been implicated in the antinociceptive effect of paracetamol. In the current study, we examined whether blockade of CB1 receptors prevent the analgesic activity of dipyrone, in a similar way to paracetamol. Hot-plate and tail-flick tests were used to assess the antinociceptive activity in mice. Dipyrone and WIN 55,212-2, a cannabinoid agonist, exerted significant antinociceptive effects in both hot-plate and tail flick tests. The CB1 receptor antagonist, AM-251 (3 mg/kg), at a dose which had no effect when used alone, did not alter the antinociceptive effect of dipyrone, whereas completely prevented the antinociceptive activity of WIN 55,212-2 in both thermal antinociceptive tests. Our findings suggest that, unlike paracetamol, cannabinoid CB1 receptors do not participate in the antinociceptive action of dipyrone when acute pain tests used.
... Post hoc analysis shows *P<0.05 compared to control b a classical opioid receptors. [18] The effects of naloxone might be complicated by analgesic effects of an opioid compound like morphine. As previously been confirmed, the analgesic effect of ultra-low dose is obtained by blocking excitatory opioid-receptor functions in dorsal root ganglion neurons and by blocking the autoinhibition of enkephalin release. ...
Role of nitric oxide (NO) in reversing morphine anti-nociception has been shown. However, the interaction between NO and naloxone-induced pain in the hippocampus is unknown. The present study aimed to investigate the involvement of molecule NO in naloxone-induced pain and its possible interaction with naloxone into cortical area 1 (CA1) of hippocampus.
Male Wistar rats (250-350 g), provided by Pasteur Institute of Iran, were housed two per cage with food and water ad libitum. The animals' skulls were cannulated bilaterally at coordinates adjusted for CA1 of hippocampus (AP: -3.8; L: ±1.8- 2.2: V: 3) by using stereotaxic apparatus. Each experimental group included 6-8 rats. To induce inflammation pain, the rats received subcutaneous (s.c.) injections of formalin (50 μL at 2.5%) once prior to testing. To evaluate the nociceptive effect of naloxone, the main narcotic antagonist of morphine (0.1-0.4 mg/kg) was injected intraperitoneally (i.p.) 10 min before injection of formalin. Injections of L-arginine, a precursor of NO, and N(G)-Nitro-L-arginine Methyl Ester (L-NAME), an inhibitor of NO synthase (NOS), intra-CA1, were conducted orderly prior to the administration of naloxone. The pain induction was analyzed by analysis of variance (ANOVA).
Naloxone at the lower doses caused a significant (P<0.01) pain in the naloxone-treated animals. However, pre-administration (1-2 min) of L-arginine (0.04, 0.08, 0.15, 0.3, 1.0, and 3.0 μg/rat, intra-CA1) reversed the response to naloxone. But, the response to L-arginine was blocked by pre-microinjection (1-2 min) of L-NAME (0.15, 0.3, 1.0, and 3.0 μg/rat), whilst, L-arginine or L-NAME alone did not induce pain behavior.
NO in the rat hippocampal CA1 area is involved in naloxone-induced nociception.
... In this regard, we decided to evaluate the antinociceptive mechanisms of action of convolutamydine A, and compounds 1, and 2, pre-treating animals with some drugs that interfere with those systems. Our results showed that the L-arginine-nitric oxide pathway is involved in the antinociception caused by convolutamydine A but does not participate in the effects caused by compounds 1 and 2. These results are consistent with other studies that show participation of the L-arginine-nitric oxide-cGMP system in the antinociceptive effects produced by several drugs during peripheral inflammation (Brito et al., 2006;Lorenzetti and Ferreira, 1996;Pol, 2007) and in several models of nociception (Riedel and Neeck, 2001). ...
Convolutamydine A, an oxindole that originated from a marine bryozoan, has several biological effects. In this study, we aimed to investigate the antinociceptive effects of convolutamydine A and two new synthetic analogues. Convolutamydine A and the two analogues were given orally to assess their ability to induce antinociceptive effects. Formalin-induced licking response, acetic acid-induced contortions, and hot plate models were used to characterize the effects of convolutamydine A and its analogues. Convolutamydine A (4,6-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole), compound 1 (3-(2-oxopropyl)-3-hydroxy-2-oxindole), and compound 2 (5-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole) caused peripheral antinociceptive and anti-inflammatory effects in the acetic acid-induced contortions and the formalin-induced licking models. Supraspinal effects were also observed in the hot plate model and were similar to those obtained with morphine. The peripheral effects were not mediated by the cholinergic or opioid systems. The antinociceptive effects of convolutamydine A seem to be mediated by all three systems (cholinergic, opioid, and nitric oxide systems), and the mechanism of action of compounds 1 and 2 involved cholinergic and nitric oxide-mediated mechanisms. Convolutamydine A and its analogues (compounds 1 and 2) showed good antinociceptive ability after systemic administration in acute pain models. The antinociceptive action mediated by cholinergic, opioid, and nitric oxide systems could explain why convolutamydine A, 1, and 2 retained their antinociceptive effects. The doses used were similar to the doses of morphine and were much lower than those of acetylsalicylic acid, the classical analgesic and anti-inflammatory drug. In conclusion, convolutamydine A and the two analogues demonstrated antinociceptive effects comparable to morphine's effects.
... In addition, acetaminophen is able to reduce substance P-, glutamate-, or NMDA-induced nociception in mice and rats [Bjö rkman, 1995;Choi et al., 2001]. On the other hand, the antinociceptive effect of metamizol has been related to activation of the nitric oxide-cyclic GMP in both the periphery and spinal cord [Lorenzetti and Ferreira, 1996;Aguirre-Bañ uelos and Granados-Soto, 1999], as well as a central opioidergic pathway leading to stimulation of an inhibitory descendent system [Carlsson and Jurna, 1987;Tortorici et al., 1996]. Moreover, metamizol seems to modulate the excitatory amino acid release and/or action at the spinal cord [Beirith et al., 1998]. ...
There is evidence that B vitamins produce antinociception in animals. However, potentiation of NSAID-induced antinociception by B vitamins is unclear. The current study was designed to investigate the antinociceptive interaction between a mixture of B vitamins and either acetaminophen or metamizol. Acetaminophen (56–316 mg/kg), metamizol (32–178 mg/kg), and the mixture of B vitamins (32–178 mg/kg of thiamine, pyridoxine, and cyanocobalamin in a 100:100:1 proportion, respectively) or a combination of each drug with the B vitamins mixture was administered orally to female Wistar rats, and the antinociceptive effect determined in the formalin test. Isobolographic analyses were used to define the nature of the interaction between NSAIDs and B vitamins. Oral administration of either drug produced a dose-related antinociceptive effect. Isobolographic analyses revealed that both acetaminophen or metamizol and the B vitamins mixture interacted synergistically in the formalin test, suggesting that these two combinations could be useful in treating inflammatory pain states. Drug Dev. Res. 66:286–294, 2006. © 2006 Wiley-Liss, Inc.
... ve action when tested against either phases of the formalin test. It has been reported that dipyrone reverses, in a dose-related manner, the hyperalgesia caused by subplantar injection of carrageenan and prostaglandin E into the rat paw, 2 by a mechanism which seems to be largely modulated by Ž the nitric oxide pathway Ferreira, 1993; Tonussi and . Lorenzetti and Ferreira, 1996 . Our results contrast somewhat with these reports for the inflammatory model of hyperalgesia, and show that the antinociception caused by dipyrone against formalin-induced pain is unlikely to involve an interaction with nitric oxide or a nitric . oxide-related substance because: 1 treatment of the animals with L-arginine, a precursor o ...
Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 μmol/kg, and 2.6 and 1.2 μmol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 μmol/site, and 0.4 and 0.9 μmol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 μmol/kg, 2.2 μmol/paw, 0.4 μmol/site and 0.14 μmol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 μmol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, l-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the l-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin, interaction of ATP-sensitive K+ channels, GABAB receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.
... In addition, the nitric oxide donor SIN-1, which did not produce antinociception by itself, was able to induce a significant antinociceptive effect when combined with an otherwise inactive dose of nimesulide (50 g/paw). These results confirm the participation of the NO-cyclic GMP pathway in the antinociception produced by several NSAIDs (Duarte et al., 1990(Duarte et al., , 1992Granados-Soto et al., 1995;Lorenzetti & Ferreira, 1996;Tonussi & Ferreira, 1994) and morphine (Duarte et al., 1992;Granados-Soto et al., 1997;Nozaki-Taguchi & Yamamoto, 1998). However, the activation of this pathway does not appear to be required in the antinociceptive action of all NSAIDs. ...
The involvement of the nitric oxide–cyclic GMP pathway in the peripheral antinociception induced by the COX-2 preferential inhibitor nimesulide was assessed by using the formalin test in the rat. Intraplantar administration of nimesulide in the formalin-injured paw produced a significant antinociceptive effect that was due to a local action, because nimesulide administration in the contralateral paw was ineffective. Local pretreatment of the paws with saline or NG-D-nitro-arginine methyl ester (D-NAME, the inactive isomer of L-NAME) did not affect the antinociception produced by nimesulide. However, local administration of L-NAME (a nitric oxide synthesis inhibitor) or 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) blocked the effect of nimesulide. Moreover, the antinociceptive effect of local nimesulide was potentiated by the coadministration of 3-morpholino-sydnonimine-HCl (SIN-1, a nitric oxide donor). It is concluded that nimesulide produces antinociception by a peripheral mechanism of action requiring activation of the nitric oxide–cyclic GMP pathway at the local level.
Background
Metamizole is used to relieve the visceral pain but its adverse effects limit its use. An alternative to improve its efficacy with lower doses is to combine it with a natural product as hesperidin.
Aim of the study. The aim of this study was to evaluate the antinociceptive interaction between metamizole and hesperidin in a visceral pain model using an isobolographic analysis.
Methods
Antinociception was evaluated in the writhing model using acetic acid (1%) to induce writhes in mice. Metamizole (1–316 mg/kg), hesperidin (3–300 mg/kg), or combinations with a fixed-dose ratio of 1:1 were administered intraperitoneally 30 min before the acetic acid and the number of writhes was counted for 30 min. Isobolographic analysis was employed to define the nature of the compound interaction.
Results
Metamizole and hesperidin in individual administration induced dose-dependent antinociceptive effects, reached an efficacy of 84.2 ± 5.9% and 66.3 ± 7.4%, respectively. The ED50 values calculated from their dose-response curves were 84.5 ± 22.7 and 108.9 ± 17.9 mg/kg, respectively. The analysis of DRC for the metamizole + hesperidin combination, in a ratio 1:1 showed a ED50 COMB value lower than the ED50 ADD estimated from the additivity line from the isobologram (46.7 ± 6.3 vs. 96.7 ± 11.9 mg/kg, respectively). In addition, the pharmacological interaction calculated was of 0.48. These results suggest a synergistic interaction for the antinociceptive activity of metamizole + hesperidin combination.
Conclusion
These data suggest that metamizole + hesperidin combination could be useful in treating visceral pain as it can interact synergistically using low dose of both drugs with the possibility of reducing the risk of adverse effects.
The erroneous or accidental epidural administration of substances entails a potential morbidity (1,2) and mortality risk. Once the accident has happened, there is no effective treatment; therefore, prevention and measures aimed to avoid this type of errors are the best and most effective treatment. We present the case of a patient to which an infusion of morphine and metamizol was epidurally administered during approximately 4 hours in PCA programmed for intravenous administration.
Swietenia humilis Zucc. (Meliaceae) seeds are used in Mexico for the treatment of type 2 diabetes mellitus. Mexicanolides are the main hypoglycemic and antihyperglycemic compounds of the species. This study was conducted to investigate the antihyperalgesic effect of an aqueous extract of the seeds of Swietenia humilis (SHAE) and of mexicanolide 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), using the formalin test in mice. The antihyperalgesic actions of SHAE and mexicanolide 1, as well as its possible transductional activity, were assessed in nicotinamide-streptozotocin (NA-STZ) hyperglycemic mice. Local injection of SHAE (10–177 μg) and mexicanolide 1 (0.5–3.5 μg) exhibited concentration-dependent antihyperalgesic action in NA-STZ hyperglycemic mice. Ketanserin (6 μg), a 5-HT2A/C receptor antagonist, and flumazenil (6 μg), a GABAA receptor antagonist, abolished the antihyperalgesic effect of mexicanolide 1 (3 μg). On the other hand, naloxone (3 μg), L-arginine (50 μg), and Nω-Nitro-l-arginine methyl ester hydrochloride (150 μg) diminished the antihyperalgesic effect of mexicanolide 1. The aqueous extract of the seeds possesses significant antihyperalgesic action. Compound 1 produces antihyperalgesia through GABAA, 5-HT2A/C and opioid receptors. Also, the nitrergic system is involve in the antihyperalgesic effect of 1. Data obtained with Swietenia humilis Zucc. seeds give evidence of its potential for pain associated with diabetes treatment.
Inflammatory hyperalgesia is the common denominator of all types of inflammatory pain. Hyperalgesia involves an integrated process that results in the functional up-regulation of the primary sensory neuron. In this circumstance, stimuli which in a normal tissue have little or no effect now activate the nociceptors to induce overt behavioural responses in experimental animals and overt pain in man. Depending upon the inflammatory stimulus and the duration of the plateau of hyperalgesia, the hyperalgesia may be classified as immediate, delayed or persistent. Persistent hyperalgesia is induced by successive daily injections of a hyperalgesic stimulus which causes delayed hyperalgesia. After 6–9 daily injections the sensitivity of the nociceptor does not return to its basal level but, instead, reaches a plateau. If this hyperalgesic plateau is maintained for 7-9 days, by additional daily injections, it persists (in the absence of further injections) for more than thirty days. These observations regarding persistent hyperalgesia indicate an important role for the sensitization of the primary sensory neuron in the establishment of chronic pain and point to the importance of using effective doses of peripherally acting analgesics during the treatment of inflammatory states of long duration. The prevention of a long lasting hyperalgesic state is crucial in order to avoid the development of persistent hyperalgesia. Once the persistent hyperalgesic state is established, cyclo-oxygenase inhibitors are ineffective and the only analgesics able to inhibit the ongoing hyperalgesia are analgesics with other mechanisms of action.
The sensitisation of pain receptors is the common denominator in all types of inflammatory pain. C-Polymodal, high threshold receptors or receptors connected by fine myelinated fibers have long been associated with inflammatory hyperalgesia [1, 2]. In recent years, a new “sleeping” nociceptor associated with certain small afferent fibers has been described in deep visceral innervations (colon and bladder) and in joints [3, 4]. Sleeping nociceptors are not active in normal tissues, but are “switched on” during inflammation. This functional upregulation leads to a clinical state known as hyperalgesia. In such a situation, previously unpainful stimuli become painful.
This chapter reviews some basic concepts of NO biology that provide an understanding of the role that NO may play in the pathophysiology of chronic joint inflammation and pain perception. Rheumatoid arthritis (RA) is a chronic systemic disease of unknown etiology characterized by symmetric polyarticular inflammation of synovia-lined joints, remarkable joint swelling, deformation, and pain. Chronic pain is one of the most serious symptoms associated with RA and affects the quality of life of the patients. Prominent histopathological features of the chronically inflamed synovia include neovascularization, hyperemia, infiltration of large numbers of leukocytes, and bone and cartilage degradation. Coincident with this extensive inflammatory infiltrate is the enhanced expression of the inducible isoform of nitric oxide synthase (iNOS) and the sustained overproduction of the free radical, nitric oxide (NO). NO modulates the inflammatory response directly or indirectly and plays an important role in pain perception. Therefore, there is increasing interest in defining the role that it may play in the pathogenesis of RA and chronic pain.
Objective: This article presents the current knowledge of pharmacology and clinical effects of Metamizol (Dipyrone) in dogs, cats and rodents. In the last years Metamizol has experienced a revival especially in human medicine. For long times Metamizol was known as a weak analgesic with especially antipyretic effects. The pharmacological effects were unknown for a long time. Today it is proven that central and peripheral effects are responsible for the potent analgesic efficacy of Metamizol. Opioiderg pathways and inhibition of the cyclooxygenases are proved mechanisms for the effects of this drug. Metamizol also shows antipyretic, weak antiphlogistic, spasmolytic and anticonvulsive effects. The analgesic efficacy is comparable to that of opioids. The side-effect of hypotension after intravenous injection can be avoided by slow injection. Agranulocytosis was never seen in veterinary medicine until now and is a side effect with an incidence of only 0.008% in human medicine. The gastro-intestinal tolerance of Metamizol is very good. Conclusion and clinical relevance: This article shows that Metamizol is an analgesic which is also very effective and well tolerated in veterinary patients.
Previous work has shown that nitric oxide (NO) mediates the antinociceptive effect of Crotalus durissus terrificus venom on carrageenin-induced hyperalgesia. In the present study the role of constitutive neuronal or of inducible form of nitric oxide synthase on venom effect was determined. The rat paw prostaglandin E2 (PGE2)-induced mechanical hyperalgesia model was used for nociceptive evaluation. The venom (200 μg/kg) administered per oz immediately before prostaglandin induced antinociception that persisted for 120 h. The characterisation of the antinociceptive effect of the venom in this model of hyperalgesia showed that κ and δ-opioid receptors are involved in this effect. 7-nitroindazole (7-NI), a neuronal nitric oxide synthase (NOS) inhibitor, but not L-N6-(1-iminoethyl)lysine (L-NIL), an inhibitor of the inducible form of NOS, injected by intraplantar (i.pl.) route, antagonized the antinociceptive effect of the venom. The i.pl. administration of 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a seletive guanylate cyclase inhibitor, blocked antinociception, whereas Rp-cGMP triethylamine, a cGMP-dependent protein kinase inhibitor, partially reversed this effect. These data indicate that peripheral κ- and δ-opioid receptors are involved in the antinociceptive effect of Crotalus durissus terrificus on prostaglandin E2-induced hyperalgesia. Peripheral nitric oxide, generated by neuronal NO synthase, and cGMP/PKc are responsible, at least partially, for the molecular mechanisms of venom effect.
A dor pós-operatória é uma dor aguda de difícil controle efetivo. O objetivo deste estudo foi avaliar, comparativamente com a literatura internacional, a incidência de dor pós-operatória nos pacientes submetidos a operações do aparelho digestivo, tratados com os analgésicos e anti-inflamatórios padronizados no Hospital de Clínicas da UFPR. Cem pacientes de ambos os sexos, com idade entre 19 e 65 anos, foram acompanhados desde a Unidade de Recuperação Pós- Anestésica Imediata até a alta hospitalar, ou até 72 horas após a cirurgia, através de ensaio duplamente encoberto com perguntas verbais sobre a presença e a intensidade da dor. Foi comparado o índice de dor dos pacientes que receberam dipirona e dipirona associada a cetoprofeno ou dipirona associada a tramadol ou dipirona associada a cetoprofeno e tramadol nos momentos determinados. De 91 pacientes analisados na Unidade de Recuperação Pós-anestésica Imediata, 33 reportaram dor. Entre os 93 pacientes observados desde o retorno à unidade de internação até a primeira administração de medicação do dia seguinte, 30 apresen-taram dor. No primeiro dia do período pós- operatório, 93 pacientes foram acompanhados, sendo encontrados 24 pacientes com dor. No segundo dia, de 37 pacientes internados, 11 continuavam com dor. Não houve diferença estatisticamente significativa entre os pacientes que receberam dipirona isolada ou associada a outros medicamentos. O presente estudo demonstrou que a incidência de dor aguda contínua pós-operatória nos pacientes do Hospital de Clínicas da Universidade Federal do Paraná tratados com os analgésicos e anti- inflamatórios padronizados foi de trinta por cento, margem mínima indicada na literatura internacional.
The pathophysiology of chronic inflammatory pain remains poorly understood. In this context, we developed an experimental model in which successive daily injection of prostaglandin E2 (PGE2) for 14 days into rat hind paws produces a persistent state of hypernociception (i.e. decrease in mechanical nociceptive threshold). This state persists for more than 30 days after discontinuing PGE2 injection. In the present study, we investigated the participation of nuclear factor kappa B (NF-κB), in the maintenance of this process. Mechanical hypernociception was evaluated using the electronic von Frey test. Activation of NF-κB signaling was measured through the determination of NF-κB p65 subunit translocation to the nucleus of dorsal root ganglion neurons (DRG) by immunofluorescence and western blotting. Herein, we detected an increase in NF-κB p65 subunit translocation to the nucleus of DRG neurons along with persistent inflammatory hypernociception compared with controls. Intrathecal treatment with either dexamethasone or PDTC (NF-κB activation inhibitor) after ending of the induction phase of the persistent inflammatory hypernociception, curtailed the hypernociception period as well as reducing NF-κB p65 subunit translocation. Treatment with antisense oligonucleotides against the NF-κB p65 subunit for 5 consecutive days also reduced persistent inflammatory hypernociception. Inhibition of PKA and PKCε reduced persistent inflammatory hypernociception, which was associated with inhibition of NF-κB p65 subunit translocation. Together these results suggest that peripheral activation of NF-κB by PKA and PKC in primary sensory neurons plays an important role in maintaining persistent inflammatory pain.
Objective and design:
The aim of this study was to investigate the possible involvement of the NO/cGMP/PKG/KATP+ pathway, cannabinoids and opioids in remote antinociception associated with 2,4,6-trinitrobenzene sulph onic acid (TNBS)-induced colitis.
Methods:
TNBS-induced colitis was induced by intracolonic administration of 20 mg of TNBS in 50% ethanol. After induction, carrageenan (500 μg/paw) or prostaglandin (PG) E2 (100 ng/paw) was injected in the rat's plantar surface and hypersensitivity was evaluated by the electronic von Frey test. Rats were pre-treated with L-Noarg one hour before carrageenan injection. L-Arginine was given 10 min before L-Noarg injections. ODQ, KT 5823, glibenclamide (Glib), naloxone and AM 251 or AM 630 were administered 30 min prior to carrageenan or PGE2 treatments.
Results:
Colitis induction by TNBS reduced PGE2 or carrageenan-induced hypersensitivity. Antinociception produced by TNBS-induced colitis was reversed significantly (P<0.05) by L-Noarg, ODQ, KT 5823, glibenclamide, naloxone, AM251 and AM630 treatments.
Conclusions:
TNBS-induced colitis causes antinociception in the rat paw. This disorder appears to be mediated by activation of the NO/cGMP/PKG/KATP pathway, endocannabinoids and endogenous opioids. This information may contribute to a better understanding of peripheral neurological dysfunctions occurring in Crohn's disease.
Objectives:
The relationship between epilepsy and inflammation is known, and it has been reported that there is an increase in cyclooxygenase (COX) levels in epilepsy. We aim to reveal the anticonvulsant effects of dexketoprofen in pentylenetetrazol (PTZ)-induced seizures in rats.
Materials and methods:
Forty-eight male Sprague-Dawley rats, 24 of them for EEG recording and 24 of them are for behavioral studies, were randomly divided in two groups: Group A for EEG recordings and Group B for behavioral assessment. A weight of 70 mg/kg PTZ was used for behavioral studies after dexketoprofen administration. Thirty-five milligrams per kilogram PTZ were used for EEG recording after dexketoprofen administration. The electrodes were implanted on dura over the left frontal cortex and the reference electrode was implanted over the cerebellum for EEG recording. The Racine convulsion scale (RCS), first myoclonic jerk (FMJ) onset time, and spike percentages were evaluated between the two groups.
Results:
There was a significant (P< 0·05) difference between the RCS, FMJ onset time (P< 0·001), and spike percentage (P< 0·05) between the groups (Group 2 compared with Groups 3 and 4).
Conclusion:
Dexketoprofen has an antiepileptic feature and this effect increases as the dosage increases, however it is currently unknown through which mechanism this drug shows its anticonvulsant effect. Dexketoprofen, in the group of NSAIDs, shows an anticonvulsant effect on PTZ-induced epilepsy model. This study suggests that dexketoprofen can preferably be used with NSAIDs for epileptic patients in clinical practice.
An efficient method to obtain 4-alkoxy-2-oxo-but-3-enoic acid ethyl esters [EtO 2 CC(O)C(R 2)=C(R 1)OR, where R = Me, Et; R 1 = Me, Ph, 4-MeC 6 H 4 , 4-BrC 6 H 4 , 4-FC 6 H 4 ; R 2 = H, Me] from the acylation of enol ethers or acetals with ethyl oxalyl chloride is reported. The cyclocondensation reaction of these substrates and their trifluoromethylated analogues [CF 3 C(O)C(R 2)=C(OR)R 1 ] with salicylic hydrazide furnished a series of ethyl 5-hydroxy-1-(2-hydroxybenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylates and 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(2-hydroxybenzoyl) pyrazoles, respectively. The structure of the compounds was supported by crystallographic data. Orally administrated, one of each of the series of pyrazoles (R 2 = H, R 1 = Me) showed significant analgesic effects in the writhing test in mice. The decrease in pain-related behavior obtained was close to that achieved with aspirin activity.
It is well known that a multitude of ligands and receptors are involved in the nociceptive system, and some of them increae,
whereas others inhibit the pain sensation both peripherally and centrally. These substances, including neurotransmitters,
neuromodulators, hormones, cytokines, and the like, may modify the activity of nerves involved in the pain pathways. The organism
itself can express very effective antinociception under different circumstances (e.g., stress), and during such situations
the levels of various endogenous ligands change. Accordingly, a very exciting field of pain research relates to the roles
of endogenous ligands. This chapter provides a comprehensive overview of the endogenous ligands that can produce antinociception,
discusses their effects on different receptors and focuses on their action in different parts of the pain pathways. The results
show that the net effect of a ligand is determined by the activation/inhibition of the different types of receptors and the
location of these receptors, however, only a part of the endogenous substances has been characterized extensively in this
respect.
KeywordsPain-Receptor-Endogenous-Antinociception
The antinociceptive activity of an inhibitor of phosphodiesterase 5 alone or combined with morphine was assessed in the formalin test. Local administration of 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3,4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, inhibitor of phosphodiesterase 5) produced a dose-dependent antinociceptive effect in the second phase of the formalin test in female Wistar rats. In contrast, morphine produced antinociception in both phases. Sildenafil significantly increased the morphine-induced antinociception. The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paw was ineffective. Pretreatment of the paws with NG-l-nitro-arginine methyl ester (l-NAME, nitric oxide (NO) synthesis inhibitor), 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or naloxone blocked the effect of the combination. Results suggest that opioid receptors, NO and cyclic GMP are relevant in the combination-induced antinociception. In conclusion, sildenafil produced antinociception and increased that produced by morphine, probably through the inhibition of cyclic GMP degradation.
The aim of this study was to improve the mustard oil (MO) induced temporomandibular joint (TMJ) nociception model and to investigate the potential analgesic activity of systemic dipyrone and tramadol on the nociceptive behavioral responses induced by injection of low concentrations of the MO into the rat TMJ region. TMJ injection of 2.5% MO produced a significant nociceptive behavior expressed by head flinching and orofacial rubbing. This activity was related to the MO injection since mineral oil (vehicle) did not elicit response. Local application of the lidocaine N-ethyl bromide quaternary salt, QX-314 (2%) and systemic administration of morphine (4 mg/kg) significantly reduced the MO-induced nociceptive responses, validating the nociceptive character of the behaviors. The pretreatment with systemic dipyrone (19, 57 or 95 mg/kg) as well as tramadol (5, 7.5 or 10 mg/kg) was effective in decreasing the nociceptive behavioral responses induced by the injection of MO into the rat TMJ. In conclusion, TMJ injection of low concentrations of MO in rats produces well defined and quantifiable nociceptive behaviors constituting a reliable behavioral model for studying TMJ pain mechanisms and testing analgesic drugs. The results also suggest that dipyrone and tramadol could be effective analgesic options in the management of TMJ pain.
The effect of dipyrone (metamizol) on cell viability was evaluated in human leukocyte cell lines upon different apoptotic treatments: arachidonic acid (AA), cycloheximide (CHX), tumor necrosis factor (TNF) and ultraviolet (UV) irradiation. Dipyrone had a dual effect: at high concentrations (beyond 300 μM), it was cytotoxic, leading to apoptosis, whereas at lower concentrations (37.5–300 μM), it was cytoprotective, delaying the loss of membrane integrity triggered by arachidonic acid (100–200 μM) and UV irradiation and the cytotoxicity of cycloheximide (25–50 μM). No effect of dipyrone was found on TNF-induced cytotoxicity (250 ng/ml). The cytoprotective effect of dipyrone is associated with a decrease in DNA fragmentation, as assessed by electrophoresis of genomic DNA and by flow cytometry; a reduction in the percentage of condensed nuclei, as evaluated by DNA staining with Hoescht 33342 and a decrease in poly(ADP)-ribose polymerase (PARP) cleavage, as assessed by Western blotting. The cytoprotective effect of dipyrone on leukocyte apoptosis occurs at concentrations usually found for the main active metabolite of the drug and may have implications on the therapeutic and side effects caused by this agent.
The peripheral and central effects of some non-steroid anti-inflammatory drugs, aspirin, indomethacin, paracetamol and phenacetin were studied by comparing their intraplantar and intracerebroventricular effects on hyperalgesia induced by carrageenin injected into the rat paw. Hyperalgesia was measured by a modification of the Randall-Selitto test. The agents tested had antialgesic effects when given by any route. Their intraventricular administration enhanced the antialgesic effect of anti-inflammatory drugs administered into the paw. Previous treatment of one paw with carrageenin reduced the oedema caused by a second injection of carrageenin in the contralateral paw. In contrast, it had no effect on the intensity of hyperalgesia but shortened the time necessary for it to reach a plateau. Administration of a prostaglandin antagonist (SC-19220) in the cerebral ventricles, in the rat paw or in both sites, significantly inhibited the hyperalgesia evoked by carrageenin. The maximal hyperalgesic effect of intraplantar injections of prostaglandin E2 could be further enhanced by its cerebroventricular administration. It was suggested that carrageenin hyperalgesia has a peripheral and a central component and that the cyclo-oxygenase inhibitors used may exert an antialgesic effect by preventing the hyperalgesia induced by a peripheral and/or central release of prostaglandins.
We tested the hypothesis that activation of the nitric oxide (NO)-cGMP pathway is involved in the mechanism of two directly acting non-opiate peripheral analgesics, myrcene and dipyrone, using our modification of the Randall-Selitto test. The NO inhibitor, NG-monomethyl-L-arginine (50 micrograms/paw) and methylene blue (500 micrograms/paw) abolished the analgesic effect of dipyrone and myrcene. Dibutyryl cyclic adenosine monophosphate (DbcAMP) caused a dose-dependent hyperalgesia (20, 50 and 100 micrograms/paw). Only responses to low doses of DbcAMP were inhibited by the two analgesics. Pretreatment with MY5445 (50 micrograms/paw) resulted in potentiation of the effects of both analgesics. These results support our hypothesis that the sensitivity of nociceptors may be controlled by the balance between the levels of cAMP and cGMP. Stimulation of the NO-cGMP pathway is probably the common denominator for the mode of action of peripheral analgesics which block hyperalgesia directly.
A new model of chronic hypersensitivity was developed in the rat by daily intraplantar administration of either prostaglandin E2 dopamine or isoprenaline, for a period of 2 weeks. Like other hyperalgesic mediators, dibutyryl-cAMP, when applied to the paws, caused an acute effect but did not produce persistent hypersensitivity. The persistent hypersensitive state was not affected by a typical non-steroidal anti-inflammatory drug (indomethacin), was temporarily inhibited by a centrally acting analgesic (morphine), was partially inhibited by a protein synthesis inhibitor (cycloheximide) and abolished by a single dose of peripherally acting analgesics such as dipyrone or N-methyl morphine. Once the residual hypersensitivity had been abolished with dipyrone or N-methyl morphine, a small dose of prostaglandin E2, dopamine or Interleukin-1 beta, which in normal animals causes a mild and short lived effect, restored the persistent hypersensitive state. This ability to restore the persistent effect was not observed with intraplantar administration of dibutyryl-cAMP. Our results suggest the existence of a peripheral trace of inflammatory pain, a phenomenon which may be associated with stimulation of neuronal adenylate cyclase and protein synthesis. This concept may explain part of the puzzle of chronic inflammatory pain and lead to the development of new analgesics.
Evidence is presented that neuroreceptors move bidirectionally along axons of neurons through fast axoplasmic transport mechanisms. The retrograde transport of receptor-bound signal molecules from nerve terminals to the perikaryon represents a corridor of information between synapses and the cell body of neurons. It is speculated that this process could be involved in long-term memory.
Septide and senktide are synthetic substance P (SP) agonists with extremely high selectivity for 1 of the 3 known SP receptor subtypes. When injected intrathecally, they produced dramatically different behavioural effects. Septide, the selective SP-P receptor agonist, evoked intense, compulsive scratching, biting and licking of the hind limb, with no sign of motor flaccidity, and without measurable effect on responses to noxious thermal or mechanical stimulation of the foot or tail. In contrast, senktide, the selective SP-N receptor agonist, produced profound, but transient, motor flaccidity, reduced response to noxious stimuli and, at low doses, 'wet-dog shakes.' These various symptoms, all previously associated with SP and/or synthetic SP analogues, appear therefore to derive from activation of distinct SP receptor subtypes.
Dipyrone blocked carrageenin-induced oedema and hyperalgesia in a dose-dependent manner. In contrast with indomethacin, paracetamol and acetyl salicylic acid, much lower doses of dipyrone were necessary for blocking hyperalgesia (ED50 = 19 mg/kg, i.p.) than oedema (180 mg/kg, i.p.) Dipyrone administered intraperitonially or intraplantarly was able to antagonise PGE2-, isoprenaline- and calcium chloride-induced hyperalgesia, effects which are not observed with non-steroid anti-inflammatory drugs. Systemic or local administration of dipyrone had no effect upon Db-cAMP-induced hyperalgesia while a centrally acting analgesic, morphine, given systemically, was highly effective. These results support our suggestion that the mechanism of action of dipyrone is different from that of classical non-steroidal anti-inflammatory drugs. Although the site of action is peripheral its analgesic effect does not derive from inhibition of the synthesis of prostaglandins but is exerted via direct blockade of the inflammatory hyperalgesia.
The study was carried out to provide further evidence that the two pyrazolone derivatives, metamizol and aminophenazone, produce central antinociceptive effects by stimulating inhibition descending from the periaqueductal grey (PAG) to the spinal cord. Experiments were carried out on rats in which the tail-flick response to radiant heat, nociceptive activity in ascending axons of the spinal cord, and activity of neurones in the PAG and the substantia nigra were studied. Microinjection of procaine (10 micrograms) into the PAG reduced the tail-flick latency and abolished the increase in latency caused by i.p. injection of metamizol (40 mg/kg) and aminophenazone (150 mg/kg); it did not significantly reduce the antinociceptive effect of i.p. injection of morphine (2 mg/kg). Threshold doses of morphine (1 and 2 micrograms) administered by intrathecal (i.t.) injection potentiated the effect of threshold doses of metamizol injected i.p. (10 mg/kg) or into the PAG (10 micrograms) in the tail-flick test. Morphine (2 micrograms) injected i.t. potentiated the effect of i.v. injection of metamizol (80 mg/kg) on nociceptive activity in ascending axons by eliminating the stimulant effect of metamizol on about one third of the axons. Threshold doses of morphine injected i.t. failed to potentiate the antinociceptive effect of aminophenazone (50 mg/kg) injected i.p. in the tail-flick test. The results support the view that metamizol and aminophenazone activate pathways descending from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level.
The pyrazolone derivative, metamizol (dipyrone), possesses analgesic, antipyretic, anti-inflammatory and spasmolytic properties. It is often classified as peripherally acting. To test the possibility that a central action of the drug contributes to its antinociceptive and analgesic effects, experiments were carried out in which the tail-flick response to radiant heat, flexor reflex activity in the tibialis anterior muscle and activity in ascending spinal axons evoked by stimulation of afferent C fibres in the sural nerve, and activity of neurones in the periaqueductal grey matter and the substantia nigra were assessed in rats. Metamizol administered by intraperitoneal (i.p.; 10, 20 and 40 mg/kg) or intrathecal (i.t.; 50 to 400 micrograms) injection to intact rats dose-dependently prolonged the tail-flick latency. Administration by i.t. injection to spinal rats was without effect. Intravenous (i.v.) injection of metamizol (140 mg/kg) reduced flexor reflex activity in intact animals, while an i.t. injection to spinal rats was ineffective at a low dose (100 micrograms) or enhanced the reflex activity at a higher dose (400 micrograms). Activity in ascending axons responding to afferent C fibre stimulation was mostly depressed by i.t. injection of metamizol (40, 80 and 140 mg/kg) in rats with an intact spinal cord. Ascending activity was increased by i.t. injection of the drug (100 and 200 micrograms) to spinal rats. Metamizol (140 mg/kg) i.v. increased the activity of neurones in the PAG and reduced that of neurones in the substantia nigra. Metamizol administered by microinjection into the PAG prolonged the tail-flick latency (15-100 micrograms) and depressed C fibre-evoked activity in ascending axons (100 micrograms). The results suggest that a central action is involved in the analgesic effect of metamizol and that this central action manifests itself by an activation of inhibition originating in the PAG.
The intraventricular injection of 1–4 μg of bradykinin caused an increase in mean arterial blood pressure of unanaesthetized rats. Hypertensive effects also followed the intraventricular injection of eledoisin, kallidin or norepinephrine. The blood pressure rise caused by intraventricular bradykinin was partially antagonized by morphine, diphenhydramine or intraventricular pyrilamine and abolished by intraventricular phentolamine. but not affected by atropine and intraventricularly injected capsaicin. hexamethonium, propranolol or methysergide. These results suggest that the hypertensive response to intraventricular bradykinin is mediated by central alpha adrenergic and histaminergic mechanisms.
Electrophysiological experiments in anesthetized cats and rats were performed in order to study the effects of dipyrone on single afferent fibers from the knee joint and on spinal cord neurons with knee joint input. The neurons were activated and/or rendered hyperexcitable by an acute inflammation in the knee joint. In the joint nerve in cats, intravenous dipyrone (25-100 mg/kg) reduced ongoing activity in 10/12 thinly myelinated afferents but only in 1/10 unmyelinated afferents; the responses to movements of the inflamed knee were reduced in 8/10 thinly myelinated but only in 3/10 unmyelinated units. The reduction of activity was significant 20-30 min after application and was maximal at 60-180 min. In the spinal cord of spinalized cats, intravenous dipyrone (25-100 mg/kg) reduced ongoing activity and/or responses to pressure onto the inflamed knee in 14/16 neurons and in non-spinalized rats similar effects were seen in 10/11 neurons. Effects on spinal cord neurons started 5-10 min after application and were maximal after 20-40 min. These data show pronounced suppression of inflammation-induced nociception by dipyrone and they suggest that the spinal cord is a major site of action of this compound.
Central mechanism of the hyper-tensive action ofintraventricular bradykinin in the unanaesthe-tized rat
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Correa FMA, Graeff FG. Central mechanism of the hyper-tensive action ofintraventricular bradykinin in the unanaesthe-tized rat. Neuropharmacology 1974;13:65-9.