Antinociceptive effects of novel histamine H₃ and H₄ receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse

Abstract

We describe a therapeutic use for new H (E-162) and H receptor (TR-7) antagonists in neuropathy. Targeting H and H receptors enhanced morphine analgesia, consistent with multimodal pain therapy.

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

“…Moreover, the similar main metabolic pathway-demethylation at the N-methylpiperazine moiety (the M1 metabolite) was determined for both the 5-HT 6 R ligands by MS and MS/MS analyses (Table 3; Figures S1-S4 in Supplementary Information). That reaction was also predicted by MetaSite with the highest, 100% probability (data not shown) and was observed in our previous investigations on the metabolism of 1,3,5-triazine-methylpiperazine derivatives [22,27]. Other metabolic pathways included hydroxylations (both compounds) and dehydrogenation (KMP-10).…”

Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain

“…Although most studies suggest that the systemic use of histamine H3 receptor antagonists produces inhibitory effects on nociceptive responses in neuropathic pain (Farzin and Nosrati, 2007;Chaumette et al, 2018;Popiolek-Barczyk et al, 2018), there is evidence that activation of H3 receptors has inhibitory effects on pain (Cannon et al, 2003). Interestingly, chronic oral administration of S38093 or A-960656, selective H3 receptor antagonist/inverse agonists, increased the paw withdrawal threshold to mechanical stimuli in neuropathic and inflammatory pain models, showing similar effects to gabapentin and/or pregabalin (Cowart et al, 2012;Chaumette et al, 2018).…”

“…Thus, systemic administration of JNJ 7777120, a histamine H4 receptor antagonist, reduced mechanical hypersensitivity in chronic constriction injury (CCI) and SNL neuropathic models (Hsieh et al, 2010). In addition, single doses of the selective H4 receptor antagonist TR-7 elicit a strong analgesic effect (Popiolek-Barczyk et al, 2018). By contrast, local ICV administration of the H4 receptor agonists ST-1006 and VUF8430, reduced nociceptive thresholds in mice with neuropathic pain (Sanna et al, 2015).…”

Spared nerve injury causes sexually dimorphic mechanical allodynia and differential gene expression in spinal cords and dorsal root ganglia in rats

“…The evidence on the role of H 3 receptors in NP is, however, con icting. Most studies seem to suggest that H 3 receptor antagonists and inverse agonists mediate antinociception [74,82], so this nding might not directly explain the observed sex difference in mechanical allodynia. However, some studies have shown H 3 agonists to have antinociceptive effects [83] and therefore, as one of the few PainNetworks genes displaying downregulation only in females, Hrh3 is of future interest.…”

“…Several ion channels and neurotransmitter systems are important in the pathophysiology of NP and targets for its treatment. Ca v α 2 δ 1 , for which Thrombospondin 4 is the endogenous ligand, α7 nicotinic receptor and histamine 3 receptors have been studied as target proteins for drugs for NP [72][73][74]. Interestingly, the biological process "neuronal action potential" was only altered in females while "regulation of synaptic transmission, GABAergic" showed a change only in males, and "positive regulation of synaptic transmission, glutamatergic" was altered in both sexes.…”