Contribution of the peripheral 5-HT 2A receptor to mechanical hyperalgesia in a rat model of neuropathic pain.
We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT 1A receptor antagonist, (-)-pindolol, a 5-HT 1A/1B receptor antagonist, and tropisetron, a 5-HT(3/4) receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT 2A receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In spite of its high affinity for the 5-HT 2A receptor, methysergide only slightly elevated the pain threshold in the hyperalgesic hind limb. Pre-treatment with methysergide significantly antagonized the inhibitory effect of sarpogrelate on hyperalgesia. Furthermore, the 5-HT 2A receptor specific binding activity of 3H-ketanserin determined for the hyperalgesic hind limb did not differ from that of the normal hind limb. From these results, we propose that the 5-HT 2A receptor in the hyperalgesic hind paw function as an agonist-independent active receptor following constriction of the sciatic nerve, and that sarpogrelate and ketanserin act as inverse agonists of this receptor and suppress its activation. Methysergide may act as a neutral antagonist that blocks the effect of inverse agonists on the 5-HT 2A receptor.
Nitanda
Aya
A
Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
Yasunami
Naho
N
Tokumo
Kohji
K
Fujii
Hiromitsu
H
Hirai
Takao
T
Nishio
Hiroaki
H
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D003714:Denervation; D004195:Disease Models, Animal; D004347:Drug Interactions / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007650:Ketanserin / Q000494:pharmacology; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000378:metabolism* / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013386:Succinates / Q000494:pharmacology
D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013386:Succinates; C064294:sarpogrelate; D007650:Ketanserin