Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury.
OBJECTIVE
Histamine is a chemical mediator that acts at four known types of histamine receptors and has been widely implicated in the development of nociception and neuropathic pain. Blocking histamine H(1) and H(2) receptors has been shown to reduce hyperalgesia following nerve injury, but the role of histamine H(3) and H(4) receptors in neuropathic pain has not been studied. Here, we used blockers of histamine H(3) and H(4) receptors to assess their effects on neuropathic pain behavior and mast cell numbers following peripheral nerve injury. In addition, we assessed the effect of activating H(4) receptors on neuropathic pain behavior.


METHODS
Rats were subjected to a partial ligation of the sciatic nerve, a model of neuropathic pain, and were treated either systemically or locally (hindpaw) with the H(3)/H(4) receptor inverse agonist thioperamide, the specific H(4) receptor antagonist JNJ 7777120, or the H(4) receptor agonist VUF 8430. Measurements of mechanical hyperalgesia were carried out by Randall-Selitto test for 1-3 weeks, and sciatic nerve tissues were analyzed for numbers of intact mast cells by histology at 9 h after surgery.


RESULTS
Rats treated with thioperamide or JNJ 7777120 showed significantly enhanced mechanical hyperalgesia after partial ligation of the sciatic nerve. The number of intact mast cells in the injured nerve of these rats was higher than in control rats suggesting reduced mast cell degranulation, but was still significantly lower than in intact nerves. Rats treated with VUF 8430 showed significantly reduced mechanical hyperalgesia.


CONCLUSIONS
We propose that the increase in mechanical hyperalgesia produced by thioperamide and JNJ 7777120 and the decrease in mechanical hyperalgesia produced by VUF 8430 may represent a direct effect of these agents on mechanospecific primary afferents, or an indirect effect of these agents via injury-induced inflammation.
Smith
Fiona M
FM
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Haskelberg
Hila
H
Tracey
David J
DJ
Moalem-Taylor
Gila
G
D000818:Animals; D006146:Guanidines / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology*; D006930:Hyperalgesia / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008026:Ligation; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D009437:Neuralgia / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D012584:Sciatic Nerve / Q000166:cytology / Q000293:injuries*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D006146:Guanidines; D006633:Histamine Antagonists; C498828:Hrh4 protein, rat; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; C516215:S-(2-guanidylethyl)isothiourea; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D013890:Thiourea; C052075:thioperamide