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Intraspinal injection of GSK189254 (10 nmol in 0.5 l) did not affect the von Frey-evoked (10 g) (A) and spontaneous (B) activity of WDR neurons in SNL rats (n 9).
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There is growing evidence supporting a role for histamine H(3) receptors in the modulation of pathological pain. To further our understanding of this modulation, we examined the effects of a selective H(3) receptor antagonist, 6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide (GSK189254), on spinal neurona...
Context in source publication
Context 1
... Injections of GSK189254 in SNL Rats. The 10-nmol dose of GSK189254 did not alter the spontane- ous or evoked (10-g von Frey hair) firing of WDR neurons when injected directly into spinal tissue close to the recording microelectrode (Fig. 6). The concentration of GSK189254 in- jected intraspinally was the same as that injected into the LC (10 nmol in 0.5 l). ...
Citations
... The WDR neurons exhibit a high sensitivity to 5-HT, which is dependent on the involvement of supraspinal structures. 117 However, the antinociceptive and pronociceptive effects of the descending serotonergic pathway in pain modulation remain controversial. 118 According to multiple studies, there are notable variances in the effects of various subtypes of 5-HT receptors on the A-components, C-components, and postdischarges of WDR neurons. ...
The spinal dorsal horn (SDH) transmits sensory information from the periphery to the brain. Wide dynamic range (WDR) neurons within this relay site play a critical role in modulating and integrating peripheral sensory inputs, as well as the process of central sensitization during pathological pain. This group of spinal multi-receptive neurons has attracted considerable attention in pain research due to their capabilities for encoding the location and intensity of nociception. Meanwhile, transmission, processing, and modulation of incoming afferent information in WDR neurons also establish the underlying basis for investigating the integration of acupuncture and pain signals. This review aims to provide a comprehensive examination of the distinctive features of WDR neurons and their involvement in pain. Specifically, we will examine the regulation of diverse supraspinal nuclei on these neurons and analyze their potential in elucidating the mechanisms of acupuncture analgesia.
... Most behavioral tests indicate that H 3 R antagonists/inverse agonists do not have any antinociceptive effects in naïve animals, suggesting that H 3 R are not involved or tonically activated in nociception, but are critical for pathological pain states associated with tissue damage and inflammation [40,58]. In the hot plate test, where animals' tissues are intact and pain has a strong nociceptive character, E153 was active only at the highest applied dose. ...
Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or μ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood–brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism.
... No effect was detected following GSK189254 treatment in the uninjured contralateral side, indicating a prominent contribution of H 3 R-mediated events in chronic pain states rather than in the physiological perception of nociception. This hypothesis is further corroborated by results from behavioral studies that indicated the lack of induction of analgesia in healthy mice by H 3 R antagonists [3,27] and an unaltered mechanical pain threshold in H 3 RKO mice [28]. ...
... administration of the compound attenuated pain perception in models of neuropathic pain and osteoarthritis [13,32]. In addition, another important site of action of GSK189254 has been reported to be the LC [27]. Consistent with these observations, i.t and intra-LC administration of GSK189254 reduced both mechanical and thermal allodynia in SNI mice. ...
Growing evidence points to the histamine system as a promising target for the management of neuropathic pain. Preclinical studies reported the efficacy of H3R antagonists in reducing pain hypersensitivity in models of neuropathic pain through an increase of histamine release within the CNS. Recently, a promising efficacy of H4R agonists as anti-neuropathic agents has been postulated. Since H3R and H4R are both localized in neuronal areas devoted to pain processing, the aim of the study is to investigate the role of H4R in the mechanism of anti-hyperalgesic action of the H3R antagonist GSK189254 in the spared nerve injury (SNI) model in mice. Oral (6 mg/kg), intrathecal (6 µg/mouse), or intra locus coeruleus (LC) (10 µg/µL) administration of GSK189254 reversed mechanical and thermal allodynia in the ipsilateral side of SNI mice. This effect was completely prevented by pretreatment with the H4R antagonist JNJ 10191584 (6 µg/mouse i.t.; (10 µg/µL intraLC). Furthermore, GSK189254 was devoid of any anti-hyperalgesic effect in H4R deficient mice, compared with wild type mice. Conversely, pretreatment with JNJ 10191584 was not able to prevent the hypophagic activity of GSK189254. In conclusion, we demonstrated the selective contribution of H4R to the H3R antagonist-induced attenuation of hypernociceptive behavior in SNI mice. These results might help identify innovative therapeutic interventions for neuropathic pain.
... The involvement of H 3 receptors in neuropathic pain has been implicated using a range of H 3 receptor antagonists/inverse agonists (Table 1) agonists restores LC and decreases α 2 adrenoceptor activity, respectively, potentially leading to relief in neuropathic pain hypersensitivity (Chaumette et al., 2018;Wei et al., 2010). To further support this proposed mechanism, it was shown that bilateral lesion of the LC, transection of the spinal cord, or direct injection of a α 2 agonist (fadolmidine) into the LC reversed the antihyperalgesic effect produced by H 3 receptor antagonists, A-960656 or GSK189254 (Chaumette et al., 2018;McGaraughty, Chu, Cowart, & Brioni, 2012;Wei et al., 2014 Gemkow et al., 2009;Giannoni et al., 2010). ...
... Interestingly, the majority of the behavioural observations published indicate that H 3 receptor antagonists/inverse agonists do not produce any antinociceptive effects in naïve rodents, suggesting a possibility that H 3 receptors are not involved or tonically activated in nociception (at least in relation to acute mechanical nociception), but are critical for pathological pain states, particularly for mechanical hypersensitivity (Chaumette et al., 2018;McGaraughty et al., 2012). ...
... H 3 receptor blockade reduces spontaneous neu-ronal firing and decreases responses of spinal nociceptive neurons to mechanical stimulation. Previously, it was reported that this effect is mainly mediated via supraspinal sites, including locus coeruleus, whose activity modulates the functions of spinal neurons [81]. ...
... The potential role of H 3 receptors in nociception has been studied in preclinical models of neuropathic pain using various H 3 receptor agonists and antagonists [81,82,83]. Available results suggest that, although these agents reduce allodynia and hyperalgesia [81], their efficacy strongly depends on the site of administration. ...
... The potential role of H 3 receptors in nociception has been studied in preclinical models of neuropathic pain using various H 3 receptor agonists and antagonists [81,82,83]. Available results suggest that, although these agents reduce allodynia and hyperalgesia [81], their efficacy strongly depends on the site of administration. On the other hand, inverse agonists of H 3 receptors: GSK189254 (4, Fig. 1) and GSK334429 (12, Fig. 5) showed efficacy in animal models of surgically-and virally-induced neuropathic pain [81,82,84] pointing out a possible application for these short-acting and poorly brain-penetrating ligands. ...
With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H3 receptor antagonists has clearly increased. Several combinations of different H3R pharmacophores with pharmacophoric elements of other G-protein coupled receptors, transporters or enzymes have been synthesized by numerous pharmaceutical companies and academic institutions. Since central nervous system disorders are characterized by diverse physiological dysfunctions and deregulations of a complex network of signaling pathways, optimal multipotent drugs should simultaneously and peculiary modulate selected groups of biological targets. Interestingly, very recent studies have shown that some of clinically evaluated histamine H3 receptor antagonists possess nanomolar affinity for sigma-1 receptor binding sites, suggesting that this property might play a role in their overall efficacy. The sigma-1 receptor, unusual and yet obscure protein, is supposed to be involved in numerous CNS pathologies through neuroprotection and neuroplasticity. These two different biological structures, histamine H3 and sigma-1 receptors, combined can represent potential fruitful target for therapeutic developments in tackling numerous human diseases.
... Moreover, the analgesic effect of S38093 is thought to be partially mediated by a2-AR desensitization in the LC, suggesting that the noradrenergic system is crucial for H3 antagonists to produce antinociception ( Chaumette et al., 2018). In fact, bilateral lesions of the LC and spinal cord transection completely inhibited the effects of H3 antagonist, on spontaneous and evoked firing of spinal neurons in neuropathic rats ( McGaraughty et al., 2012). Like H3 receptors, H4 receptor agonists and antagonists have different effects on the nociceptive response. ...
Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.
... The involvement of H 3 receptors in neuropathic pain has been implicated using a range of H 3 receptor antagonists/inverse agonists (Table 1) agonists restores LC and decreases α 2 adrenoceptor activity, respectively, potentially leading to relief in neuropathic pain hypersensitivity (Chaumette et al., 2018;Wei et al., 2010). To further support this proposed mechanism, it was shown that bilateral lesion of the LC, transection of the spinal cord, or direct injection of a α 2 agonist (fadolmidine) into the LC reversed the antihyperalgesic effect produced by H 3 receptor antagonists, A-960656 or GSK189254 (Chaumette et al., 2018;McGaraughty, Chu, Cowart, & Brioni, 2012;Wei et al., 2014 Gemkow et al., 2009;Giannoni et al., 2010). ...
... Interestingly, the majority of the behavioural observations published indicate that H 3 receptor antagonists/inverse agonists do not produce any antinociceptive effects in naïve rodents, suggesting a possibility that H 3 receptors are not involved or tonically activated in nociception (at least in relation to acute mechanical nociception), but are critical for pathological pain states, particularly for mechanical hypersensitivity (Chaumette et al., 2018;McGaraughty et al., 2012). ...
Histamine, acting via distinct histamine H1, H2, H3, and H4 receptors, regulates various physiological and pathological processes, including pain. In the last two decades, there has been a particular increase in evidence to support the involvement of H3 receptor and H4 receptor in the modulation of neuropathic pain, which remains challenging in terms of management. However, recent data show contrasting effects on neuropathic pain due to multiple factors that determine the pharmacological responses of histamine receptors and their underlying signal transduction properties (e.g., localization on either the presynaptic or postsynaptic neuronal membranes). This review summarizes the most recent findings on the role of histamine and the effects mediated by the four histamine receptors in response to the various stimuli associated with and promoting neuropathic pain. We particularly focus on mechanisms underlying histamine‐mediated analgesia, as we aim to clarify the analgesic potential of histamine receptor ligands in neuropathic pain.
Linked Articles
This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc
... 19 Besides metabolic conditions, H3R antagonists have also been evaluated for neuropathic pain, sleeping disorder, cognitive impairments, Tourette syndrome and attention deficit hyperactivity disorder (ADHD). 14,[20][21][22] For example, GSK239512 (NCT01009255), MK-0249 (NCT00420420), ABT-288 (NCT01018875) and SAR110894 (NCT01266525) were evaluated in Phase 2 clinical trials for the treatment of Alzheimer's disease, but none of them were approved due to lack of efficacy or side effects. 14 Nevertheless, recently one H3R antagonistPitolisant has been approved by the European Medicines Agency for the treatment of narcolepsy. ...
The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-Aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonist. Among all the synthesized compounds, in vitro and docking studies suggested that 4-methoxy-phenyl substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC50<0.04 μM). Compound 4c did not exhibit any activity on hERG ion channel and Pan-assay interference compounds (PAINS) liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier and in vivo studies demonstrated that 4c induces anorexia, and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.
... GSK-189254 has also been used as PET radiotracer (in the form of [ 11 C]-GSK-189254, also used as [ 11 C]-AZ12807110 by Jucaite et al. (Jucaite et al., 2013)) to assess H 3 R occupancy (Ashworth et al., 2010), and is currently used in an image-based phase I clinical trial study for investigating GSK-239512 distribution in the brain (NCT00474513). Efficacy of GSK-189254 in preclinical models of neuropathic pain has been reported (McGaraughty, Chu, Cowart, & Brioni, 2012;Medhurst et al., 2008). At present, a phase I trial has been completed for the safety and efficacy assessment of GSK-189254 in a electrical hyperalgesia model in healthy subjects in a double-blind, double-dummy, placebocontrolled, incomplete block, two period crossover study with no disclosure of the result (NCT00387413). ...
Since the discovery of the histamine H 3 receptor in 1983, tremendous advances in the pharmacological aspects of H 3 receptor antagonists/inverse agonists have been accomplished in preclinical studies. At present, there are several drug candidates that reached clinical trial studies for various indications. However, entrance of these candidates to the pharmaceutical market is not free from challenges, and a variety of difficulties is engaged with their developmental process. In this review, the potential role of H 3 receptors in the pathophysiology of various central nervous system, metabolic and allergic diseases is discussed. Thereafter, the current status for H 3 receptor antagonists/inverse agonists in ongoing clinical trial studies is reviewed and obstacles in developing these agents are emphasized.
... a P Ͻ 0.05 vs. naive; b P Ͻ 0.05 vs. sham SNL; c P Ͻ 0.01 vs. respective "paw" group; d P Ͻ 0.01 vs. CFA, SNL, and carrageenan; e P Ͻ 0.05 vs. MIA (knee); f P Ͻ 0.05 vs. MIA (paw); g P Ͻ 0.01 vs. sham MMT (knee), sham MMT (paw), and sham MIA (knee); h P Ͻ 0.05 vs. MMT (paw); i P Ͻ 0.05 vs. sham MMT (knee) using Games-Howell post hoc analysis. Each calculation is compiled from published (Boyce-Rustay et al. 2010;Brederson et al. 2018;Chu et al. 2004Chu et al. , 2011Chu et al. , 2015El-Kouhen et al. 2006;Jarvis et al. 2007Jarvis et al. , 2014McGaraughty et al. 2003McGaraughty et al. , 2006McGaraughty et al. , 2007McGaraughty et al. , 2008aMcGaraughty et al. , 2008bMcGaraughty et al. , 2009McGaraughty et al. , 2010McGaraughty et al. , 2012McGaraughty et al. , 2017Surowy et al. 2008;Xu et al. 2012Xu et al. , 2014Zhu et al. 2014) and unpublished data. modulation) had a mean level of spontaneous activity that was not significantly different from "intact" SNL or sham-SNL groups. ...
This overview compares the activity of wide dynamic range (WDR) and nociceptive specific (NS) neurons located in the deep dorsal horn across different rat models of pathological pain and following modulation by diverse pharmacology. The data was collected by our group under the same experimental conditions over numerous studies to facilitate comparison. Spontaneous firing of WDR neurons was significantly elevated (>3.7 Hz) in models of neuropathic, inflammation, and osteoarthritic pain compared to naive animals (1.9 Hz), but was very low (<0.5 Hz) and remained unchanged in NS neurons. WDR responses to low intensity mechanical stimulation were elevated in neuropathic and inflammation models. WDR responses to high intensity stimuli were enhanced in inflammatory (heat) and osteoarthritis (mechanical) models. NS responses to high intensity stimulation did not change, relative to control, in any model examined. Several therapeutic agents reduced both evoked and spontaneous firing of WDR neurons (e.g., TRPV1, TRPV3, Nav1.7, Nav1.8, P2X7, P2X3, H3), other targets affected neither (e.g., H4, TRPM8, KCNQ2/3), some only modulated evoked (e.g, ASIC1a, Cav3.2), while others decreased evoked but affected spontaneous activity only in specific models (e.g., TRPA1, CB2). Spontaneous firing of WDR neurons was not altered by any peripherally restricted compound or by direct administration of compounds to peripheral sites even though the same compounds decreased evoked activity. Compounds acting centrally were effective against this endpoint. The diversity of incoming/modulating inputs to the deep dorsal horn positions this group of neurons as an important intersection within the pain system to validate novel therapeutics.
