Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production.
At the spinal level, the involvement of nociceptin/orphanin FQ (N/OFQ) in pain transmission is controversial. JTC-801, a selective nonpeptidergic N/OFQ antagonist, is a good tool to examine the involvement of endogenous N/OFQ in pathophysiological conditions. In the present study, we studied the effect of JTC-801 on neuropathic pain induced by L5 spinal nerve transection in mice. Thermal hyperalgesia was evident on day 3 postsurgery and maintained during the 10-day experimental period. Oral administration of JTC-801 relieved the thermal hyperalgesia in neuropathic mice in a dose-dependent manner. Following L5 nerve transection, the increase in nitric oxide synthase (NOS) activity was observed in the superficial layer of dorsal horn and around the central canal in the spinal cord by NADPH diaphorase histochemistry. Using the novel fluorescent nitric oxide (NO) detection dye diaminofluorescein-FM, we confirmed that NO production increased in the spinal slice prepared from neuropathic mice and that the increase was more prominent in the ipsilateral side to the nerve transection than in the contralateral side. These increases in NOS activity and NO production in neuropathic mice were blocked by pretreatment of oral JTC-801. Although intraperitoneal injection of the nonselective NOS inhibitor NG.-nitro-L-arginine methyl ester transiently, but significantly, attenuated neuropathic hyperalgesia, inducible NOS-deficient mice showed neuropathic pain after L5 spinal nerve transection. These results suggest that N/OFQ is involved in the maintenance of neuropathic pain and that the analgesic effect of JTC-801 on neuropathic pain is mediated by inhibition of NO production by neuronal NOS.
Mabuchi
Tamaki
T
Department of Medical Chemistry, Kansai Medical University, Moriguchi 570-8506, Japan.
Matsumura
Shinji
S
Okuda-Ashitaka
Emiko
E
Kitano
Takahiro
T
Kojima
Hirotatsu
H
Nagano
Tetsuo
T
Minami
Toshiaki
T
Ito
Seiji
S
D000634:Aminoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D019793:Fluorescein; D005453:Fluorescence; D005456:Fluorescent Dyes; D007839:Functional Laterality; D018698:Glutamic Acid / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018847:Opioid Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011930:Reaction Time; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries; D013997:Time Factors; D000097629:Nociceptin
D000634:Aminoquinolines; D001549:Benzamides; D004791:Enzyme Inhibitors; D019793:Fluorescein; D005456:Fluorescent Dyes; D018698:Glutamic Acid; D009252:NADPH Dehydrogenase; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D018847:Opioid Peptides; D010446:Peptide Fragments; D000097629:Nociceptin; C414689:4,5-diaminofluorescein diacetate; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C403776:nociceptin-(1-13)-NH2, NPhe(1)-