Antinociceptive effects of novel histamine H 3 and H 4 receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse

• Published in: British journal of pharmacology 2018-07, Vol.175 (14), p.2897-2910
• Main Authors: Popiolek-Barczyk, Katarzyna, Łażewska, Dorota, Latacz, Gniewomir, Olejarz, Agnieszka, Makuch, Wioletta, Stark, Holger, Kieć-Kononowicz, Katarzyna, Mika, Joanna
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics, Opioid - therapeutic use; Animals; Drug Synergism; Drug Therapy, Combination; Female; Histamine Antagonists - therapeutic use; Male; Mice; Morphine - therapeutic use; Neuralgia - drug therapy; Neuralgia - physiopathology; Receptors, Histamine H3 - physiology; Receptors, Histamine H4 - antagonists & inhibitors; Receptors, Histamine H4 - physiology; Sciatic Nerve - injuries
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14185

The histaminergic system is a promising target for the development of new analgesics, as histamine H and H receptors are expressed in regions concerned with nociceptive transmission. Here we have determined the analgesic effects of new H and H receptor antagonists in naive and neuropathic mice. We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H receptor antagonist, E-162(1-(5-(naphthalen-1-yloxy)pentyl)piperidine) and H 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 H receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H and H receptors and determined metabolic stability. 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 H receptor antagonist. E-162 bound potently to H receptors (K  = 55 nM) and inhibited cAMP accumulation (IC  = 165 nM). TR-7 showed lower affinity for H receptors (K  = 203 nM) and IC  of 512 nM. 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.