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

BACKGROUND AND
PURPOSE: The histaminergic system is a promising target for the development of new analgesics, as histamine H3 and H4 receptors are expressed in regions concerned with nociceptive transmission. Here we have determined the analgesic effects of new H3 and H4 receptor antagonists in naive and neuropathic mice. EXPERIMENTAL APPROACH: We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H3 receptor antagonist, E-162(1-(5-(naphthalen-1-yloxy)pentyl)piperidine) and H4 receptor antagonist, TR-7(4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) were assessed on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in mice with and without CCI (7 days after injury). Effects of these antagonists on morphine analgesia were also evaluated, along with the possible participation of H1 receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H3 and H4 receptors and determined metabolic stability. KEY
RESULTS: E-162 and TR-7 attenuated nociceptive responses and profound morphine analgesia in males with CCI. These antagonists showed analgesia in naive mice (tail flick test) and produced prolonged analgesia in neuropathic females. E-162-induced analgesia was reversed by pyrilamine, an H1 receptor antagonist. E-162 bound potently to H3 receptors (Ki  = 55 nM) and inhibited cAMP accumulation (IC50  = 165 nM). TR-7 showed lower affinity for H4 receptors (Ki  = 203 nM) and IC50  of 512 nM. CONCLUSIONS AND IMPLICATIONS: We describe a therapeutic use for new H3 (E-162) and H4 receptor (TR-7) antagonists in neuropathy. Targeting H3 and H4 receptors enhanced morphine analgesia, consistent with multimodal pain therapy.