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Vol. 291, Issue 1, 308-313, October 1999

Dose-Related Opposite Modulation by Nociceptin/Orphanin FQ of Substance P Nociception in the Nociceptors and Spinal Cord

Makoto Inoue1 , Ichiro Shimohira, Akira Yoshida, Andreas Zimmer, Hiroshi Takeshima, Tsukasa Sakurada and Hiroshi Ueda

Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki, Japan (M.I., I.S., A.Y., H.U.); Section on Genetics, National Institute of Mental Health, Bethesda, Maryland (A.Z.); Department of Pharmacology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (H.T.); and Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (T.S.)

We previously reported that the intraplantar (i.pl.) application of nociceptin/orphanin FQ (N/OFQ) at extremely low doses elicited a nociception through a substance P (SP) release from nociceptor endings. In the present study, the nociception induced by SP (and N/OFQ) was abolished by intrathecal (i.t.) injection of neurokinin1 (SP receptor) antagonist, suggesting the involvement of the stimulation of nociceptive primary SP neuron and SP release into spinal synapses. On the other hand, similar low doses of N/OFQ (i.t.) exerted nociceptive responses, characterized by scratching, biting, and licking, and these responses were blocked by an neurokinin1 antagonist (i.t.) or capsaicin pretreatment or in tachykinin 1 gene knockout mice (tac1-/- mice), suggesting that N/OFQ receptor (NOR) also exists on the spinal terminals of SP neurons. When wide ranges of N/OFQ doses were used, a typical bell-shaped dose-response relationship was observed in both peripheral and central nociception tests. Furthermore, N/OFQ (1 nmol) administered i.pl. blocked SP (i.pl.)-induced flexor responses, which were abolished by pertussis toxin pretreatment or in NOR gene knockout (NOR-/- ) mice. On the other hand, N/OFQ administered i.t. blocked SP (i.t.)-induced scratching, biting, and licking in capsaicin-pretreated and tac1-/- mice, and this antinociception was abolished in NOR-/- mice. All these findings suggest that N/OFQ has biphasic actions depending on doses in the nociceptors and spinal synapses and has postsynaptic antinociceptive actions in spinal cord by modulating SP signaling.

0022-3565/99/2911-0308$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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