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Incidence of fl inching behaviour in rats after formalin injection shown in 5 min bins. In phase I (0-5 min), all the groups showed higher number of fl inches than morphine. In phase II, groups receiving L-CCBs alone showed higher fl inching behaviour than morphine. Groups, which had received L-CCB + morphine showed lower number of fl inches. Values are shown as mean ± S.E.M.
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Earlier, we had reported that co-administration of opioids and L-type calcium channel blockers (L-CCBs) like diltiazem could prove useful in the treatment of cancer pain. Much of this report was based upon earlier published work involving animal models of pain exposed to brief periods of noxious radiant heat without any tissue injury. However, pain...
Citations
... A mathematical model of the dorsal horn demonstrates that the Ca v 1.3 channel expression is essential in short-term sensitization in pain transmission, and the Ca v 1.2 channel contributes to long-term plasticity associated with neuropathic pain (Radwani et al., 2016). The co-administration of opioids and L-type blockers (morphine and nimodipine) represents a therapeutic strategy for analgesic treatment in pain relief (Kumar et al., 2010). Nevertheless, the mechanism is not well-determined since it has been observed that the co-administration of nimodipine and morphine leads to a decreased expression of Ca v 1.2 and an increase in Ca v 2.2, and in other studies, it has been demonstrated that there is a decreased level of Ca v 1.3 but not of the Ca v 1.2 and Ca v 2.2 channels (Park and Luo, 2010). ...
Neuropathic pain can appear as a direct or indirect nerve damage lesion or disease that affects the somatosensory nervous system. If the neurons are damaged or indirectly stimulated, immune cells contribute significantly to inflammatory and neuropathic pain. After nerve injury, peripheral macrophages/spinal microglia accumulate around damaged neurons, producing endogenous hydrogen sulfide (H 2 S) through the cystathionine-γ-lyase (CSE) enzyme. H 2 S has a pronociceptive modulation on the Ca v 3.2 subtype, the predominant Ca v 3 isoform involved in pain processes. The present review provides relevant information about H 2 S modulation on the Ca v 3.2 T-type channels in neuropathic pain conditions. We have discussed that the dual effect of H 2 S on T-type channels is concentration-dependent, that is, an inhibitory effect is seen at low concentrations of 10 µM and an augmentation effect on T-current at 100 µM. The modulation mechanism of the Ca v 3.2 channel by H 2 S involves the direct participation of the redox/Zn ²⁺ affinity site located in the His191 in the extracellular loop of domain I of the channel, involving a group of extracellular cysteines, comprising C114, C123, C128, and C1333, that can modify the local redox environment. The indirect interaction pathways involve the regulation of the Ca v 3.2 channel through cytokines, kinases, and post-translational regulators of channel expression. The findings conclude that the CSE/H 2 S/Ca v 3.2 pathway could be a promising therapeutic target for neuropathic pain disorders.
... This treatment also prevents the development of dependence, as shown by the reduction of the ability of naloxone to precipitate the behavioral and biochemical signs of abstinence syndrome. Besides, the block of L-type VGCCs increased the analgesic effect of opioids and interfered with morphine hyperalgesia and morphine tolerance (for review, see [10,76,77]). Additionally, diltiazem and nifedipine can prevent oxaliplatininduced cold hyperalgesia in rats [78]. ...
Pain is a complex phenomenon that is usually unpleasant and aversive. It can range widely in intensity, quality, and duration and has diverse pathophysiologic mechanisms and meanings. Voltage-gated sodium and calcium channels are essential to transmitting painful stimuli from the periphery until the dorsal horn of the spinal cord. Thus, blocking voltage-gated calcium channels (VGCCs) can effectively control pain refractory to treatments currently used in the clinic, such as cancer and neuropathic pain. VGCCs blockers isolated of cobra Naja naja kaouthia (α-cobratoxin), spider Agelenopsis aperta (ω-Agatoxin IVA), spider Phoneutria nigriventer (PhTx3.3, PhTx3.4, PhTx3.5, PhTx3.6), spider Hysterocrates gigas (SNX-482), cone snails Conus geographus (GVIA), Conus magnus (MVIIA or ziconotide), Conus catus (CVID, CVIE and CVIF), Conus striatus (SO-3), Conus fulmen (FVIA), Conus moncuri (MoVIA and MoVIB), Conus regularis (RsXXIVA), Conus eburneus (Eu1.6), Conus victoriae (Vc1.1.), Conus regius (RgIA), and spider Ornithoctonus huwena (huwentoxin-I and huwentoxin-XVI) venoms caused antinociceptive effects in different acute and chronic pain models. Currently, ziconotide is the only clinical used N-type VGCCs blocker peptide for chronic intractable pain. However, ziconotide causes different adverse effects. The intrathecal route of administration also impairs its use in a more significant number of patients. In this sense, peptides isolated from animal venoms or their synthetic forms that modulate or block VGCCs channels seem to be a relevant prototype for developing new analgesics efficacious and well tolerated by patients.
... Studies suggest that CCB blockade of postsynaptic vascular 5-HT 1A and 5-HT 2 receptors may play a key role in migraine mitigating effects (44,45). Furthermore, recent studies suggest that CCB co-administration with opioids may lead to decreased pain response by preventing the pathogenesis of opioid-induced hyperalgesia (46,47). ...
Migraine is a debilitating neurologic condition with symptoms typically consisting of unilateral and pulsating headache, sensitivity to sensory stimuli, nausea, and vomiting. The World Health Organization (WHO) reports that migraine is the 3rd most prevalent medical disorder and 2nd most disabling neurological condition in the world. There are several options for preventive migraine treatments include, but are not limited to, anticonvulsants, antidepressants, beta-blockers, calcium channel blockers, botulinum toxins, NSAIDs, riboflavin, and magnesium. Patients may also benefit from adjunct nonpharmacologic options in the comprehensive prevention of migraines, such as cognitive behavior therapy, relaxation therapies, biofeedback, lifestyle guidance, and education. Preventative therapies are an essential component of the overall approach to the pharmacologic treatment of migraine. Comparative studies of newer therapies are needed to help patients receive the best treatment option for chronic migraine pain.
... 5,6,32,34 While some studies have reported the involvement of L-type channels in pain and antinociception at the spinal level,- 35,36 systemic L-type channel blockage is not likely to have any analgesic effect. 37 With regard to potassium channels, acute application of amiodarone mainly inactivates the voltage-gated potassium channel 11.1 (Kv 11.1), and blocks the delayed rectifier potassium current. 7,8,38 Previous studies have revealed the involvement of several types of voltage-gated potassium channels, such as Kv 1, Kv 2, Kv 3, Kv 4, and Kv 7.1 in chronic and neuropathic pain. ...
Purpose: Although amiodarone is classified as a Vaughan-Williams class III antiarrhythmic drug, it has inhibitory effects on voltage-gated sodium and calcium channels and on β-adrenergic receptors. Given these pharmacological profiles, amiodarone may have analgesic properties. Most patients who are prescribed amiodarone possess multiple cardiovascular risk factors. Despite the fact that pain plays a crucial role as a clinical indicator of cardiovascular events, the effects of amiodarone on pain have not been investigated. The aim of the current study was to investigate the analgesic effects of amiodarone by using mouse models of pain in an effort to elucidate underlying mechanisms.
Methods: Adult male C57B6 mice received single bolus intraperitoneal injections of amiodarone at doses of 25, 50, 100, and 200 mg/kg, while the mice in the control group received only normal saline. The analgesic effects of amiodarone were evaluated using the acetic acid-induced writhing test, formalin test, and tail withdrawal test. In addition, the potassium channel opener NS1643, voltage-gated sodium channel opener veratrine, calcium channel opener BAYK8644, and selective β-adrenergic agonist isoproterenol were used to uncover the underlying mechanism.
Results: During the acetic acid-induced writhing test, formalin test, and tail withdrawal test, amiodarone induced analgesic responses in a dose-dependent manner. The analgesic effects of amiodarone were abolished by veratrine but not by NS1643, BAYK8644, or isoproterenol.
Conclusion: Amiodarone induced analgesic responses in a dose-dependent manner, likely by blocking voltage-gated sodium channels. These results indicate that clinical doses of amiodarone can affect nociception and may mask or attenuate pain induced by acute cardiovascular events.
... This in turn supports the crosstalk between propranolol and morphine in potentiating morphine antinociception. In fact the analgesic effect of morphine has been linked to mechanisms more than changes in the level of cAMP such as reducing neurotransmitter release at the presynaptic levels via inhibition of calcium channels (Kumar et al., 2010). Morphine also can hyperpolarize nociceptors at the postsynaptic levels through activation of potassium channels (Khanna et al., 2011). ...
Tolerance to the analgesic effect of morphine is a major clinical problem which can be managed by co-administration of another drug. This study investigated the ability of propranolol to potentiate the antinociceptive action of morphine and the possible mechanisms underlying this effect. Antinociception was assessed in three nociceptive tests (thermal, hot plate), (visceral, acetic acid), and (inflammatory, formalin test) in mice and quantified by measuring the percent maximum possible effect, the percent inhibition of acetic acid-evoked writhing response, and the area under the curve values of number of flinches for treated mice, respectively. The study revealed that propranolol (0.25–20 mg/Kg, IP) administration did not produce analgesia in mice. However, 10 mg/Kg propranolol, enhanced the antinociceptive effect of sub-analgesic doses of morphine (0.2, 1, and 2 mg/Kg, IP) in the three nociceptive tests. It also shifted the dose response curve of morphine to the left. The combined effect of propranolol and morphine was attenuated by haloperidol (D2 receptor antagonist, 1.5 mg/Kg, IP), and bicuculline (GABAA receptor antagonist, 2 mg/Kg, IP). Repeated daily administration of propranolol (10 mg/Kg, IP) did not alter the nociceptive responses in the three pain tests, but it significantly potentiated morphine-induced antinociception in the hot plate, acetic acid-evoked writhing, and in the second phase of formalin tests. Together, the data suggest that a cross-talk exists between the opioidergic and adrenergic systems and implicate dopamine and GABA systems in this synergistic effect of morphine-propranolol combination. Propranolol may serve as an adjuvant therapy to potentiate the effect of opioid analgesics.
... The specific doses of morphine and nimodipine used in these experiments were selected based on both toxicity studies conducted in our laboratory as well as previous literature. [17] ...
... Taken together, our study underscores the plasticity of brain L-type Ca 2+ channels and suggests that their upregulation might contribute to morphine dependence. [17] The effects of the Ca 2+ -channel blockers verapamil and nimodipine, on the behavioral signs of naloxone (1 mg/kg)-induced abstinence syndrome in morphine-dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured, using high-performance liquid chromatography and electrochemical detection or gas chromatography-mass spectrometry, in various brain regions of these animals. ...
Objective: To observe the effect of L‑type calcium channel blocker like
nimodipine on morphine’s withdrawal when it was administered continuously
along with morphine versus a single bolus dose of nimodipine, which was
administered at the end of the experiment before the precipitation of withdrawal
reaction in morphine‑dependent rats. Materials and Methods: Four groups
of adult male Wistar rats were rendered morphine dependent by subcutaneous
injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine
10 mg/kg intraperitoneally (ip) administered to one group once daily before
morphine administration in the entire experimental period, and another group
received nimodipine only once at the end of the experiment as a single bolus
dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was
administered ip to all the groups to precipitate withdrawal reactions. The
withdrawal reactions were evaluated and scored as per the Gellert and Holtzman
global withdrawal rating scale. Results: Nimodipine when administered as a single
bolus dose before naloxone administration in morphine‑dependant rats reduced the
features of withdrawal reactions more effectively than continuous administration
of nimodipine along with morphine throughout the experimental period.
Conclusion: We discovered that nimodipine helps in attenuating the severity of
morphine withdrawal having potential role encountered during pharmacotherapy
with morphine management of opioid dependence, well memory, impairement, cell
signaling and phosphorylation of neuron.
Keywords: Dependence and withdrawal reactions, morphine, naloxone,
... The specific doses of morphine and nimodipine used in these experiments were selected based on both toxicity studies conducted in our laboratory as well as previous literature. [17] ...
... Taken together, our study underscores the plasticity of brain L-type Ca 2+ channels and suggests that their upregulation might contribute to morphine dependence. [17] The effects of the Ca 2+ -channel blockers verapamil and nimodipine, on the behavioral signs of naloxone (1 mg/kg)-induced abstinence syndrome in morphine-dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured, using high-performance liquid chromatography and electrochemical detection or gas chromatography-mass spectrometry, in various brain regions of these animals. ...
Objective
To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats.
Materials and Methods
Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale.
Results
Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period.
Conclusion
We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron.
... The specific doses of morphine and nimodipine used in these experiments were selected based on both toxicity studies conducted in our laboratory as well as previous literature. [17] ...
... Taken together, our study underscores the plasticity of brain L-type Ca 2+ channels and suggests that their upregulation might contribute to morphine dependence. [17] The effects of the Ca 2+ -channel blockers verapamil and nimodipine, on the behavioral signs of naloxone (1 mg/kg)-induced abstinence syndrome in morphine-dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured, using high-performance liquid chromatography and electrochemical detection or gas chromatography-mass spectrometry, in various brain regions of these animals. ...
Objective: To observe the effect of L-type calcium channel blocker like nimodipine on morphine’s withdrawal bjective:
when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was
administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent
rats. Materials and Methods: Four groups of adult male Wistar rats were rendered morphine dependent by aterials and Methods:
subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine10 mg/kg intraperitoneally (ip)
administered to one group once daily before morphine administration in the entire experimental period, and
another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg
before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate
withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman
global withdrawal rating scale. Results: Nimodipine when administered as a single bolus dose before naloxone esults: administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period.
... Morphine interacts with opioid receptors and produce analgesia by hyperpolarization of interneurons, leading to a release of transmitters associated with pain transmission (Lipp, 1991). Studies in the same context have shown that Morphine-induced-analgesia is more important the presence of VGCC blockers (Kumar et al., 2010). ...
Medicinal plants are the oldest and the most common form of medication against health issues. Several studies have demonstrated that plant extracts and their secondary metabolites represent an interesting source for drug discovery. Alkaloids, a major group of naturally occurring organic nitrogen-containing bases, have been shown to be implicated in many physiological processes through the modulation of ion channels, in particular, voltage-gated calcium channels. Calcium channels are the key molecules responsible for the regulation of major intracellular processes through the mediation of calcium entry into cells in response to membrane depolarization. They are divided into two broad categories: The high (L-, N-, P-, Q-and R-types calcium channels) and the low (T-type calcium channels) threshold-activated calcium channels. However, calcium channels dysfunction can be responsible for a multitude of disorders including diabetes, several forms of cancer and epilepsy. The present article point out the scientific evidence of the effectiveness of natural alkaloids extracted from common medicinal plants including Peganum harmalaon the modulation of voltage-gated calcium channels as well as their pharmacological and therapeutic outcomes.
... However, in the present study nimodipine by itself did not induce either algesic or analgesic effect in both normal and sensitized mice. Other studies also reported that nimodipine improves analgesic effect of morphine in normal animals (Kumar, Mehra & Ray, 2010;Michaluk, Karolewicz, Antkiewicz-Michaluk & Vetulani, 1998;Shimizu et al., 2004;Zharkovsky, Katajamaki, Seppala & Ahtee, 1999). In the present study, we administered nimodipine along with morphine to investigate possible involvement of Ca 2+ channels in the decreased analgesic effect of morphine in sensitized mice. ...
Introduction
We investigated the role of ATP-sensitive potassium channels and L-type calcium channels in morphine-induced hyperalgesia after nociceptive sensitization.
Methods
We used a hotplate apparatus to assess pain behavior in male NMRI mice. Nociceptive sensitization was induced by three days injection of morphine and five days of drug free. On day 9 of the schedule, pain behavior test was performed for evaluating the effects of morphine by itself and along with nimodipine, a blocker of L-type calcium channels and diazoxide, an opener of ATP-sensitive potassium channels. All drugs were injected through an intraperitoneal route.
Results
The results showed that morphine (7.5, 10 and 15 mg/kg) induced analgesia in normal mice, which was prevented by naloxone (1 mg/kg). After nociceptive sensitization, analgesic effect of morphine (10 and 15 mg/kg) was significantly decreased in sensitized mice. The results showed that nimodipine (2.5, 5, 10 and 20 mg/kg) had no significant effect on pain behavior test in either normal or sensitized mice. However, nimodipine (20 mg/ kg) along with morphine (10 and 15 mg/kg) caused more decrease in morphine analgesia in sensitized mice. Furthermore, diazoxide by itself (0.25, 1, 5 and 20 mg/kg) had also no significant effect on pain behavior in both normal and sensitized mice, but at dose of 20 mg/kg along with morphine (10 and 15 mg/kg) decreased analgesic effect of morphine in sensitized mice.
Discussion
It can be concluded that potassium and calcium channels have some roles in decrease of analgesic effect of morphine after nociceptive sensitization induced by pretreatment of morphine.
