Vol. 305, Issue 2, 495-501, May 2003

In Vivo Pain-Inhibitory Role of Nociceptin/Orphanin FQ in Spinal Cord

Makoto Inoue, Toshiko Kawashima, Hiroshi Takeshima, Girolamo Calo, Atsuko Inoue, Yoshihiro Nakata and Hiroshi Ueda

Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan (M.I., T.K., H.U.); Department of Biochemistry and Molecular Biology, Tohoku University Graduate School of Medicine, Sendai, Japan (H.T.); Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy (G.C.); and Department of Pharmacology Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Hiroshima, Japan (A.I., Y.N.)

Because nociceptin/orphanin FQ (N/OFQ) has both pronociceptive (hyperalgesia) and antinociceptive actions in pharmacological experiments, and there is no significant difference in the nociceptive responses between NOP^/ mice and their wild-type (NOP^+/+) littermates, the physiological role of N/OFQ in pain regulation remains to be determined. Under the hypothesis that the use of molecularly distinct nociception test may reveal the pain modality-specific role of N/OFQ, we attempted to examine the physiological role of N/OFQ in pain transmission by using newly developed algogenic-induced nociceptive flexion test in NOP^/ and NOP^+/+ mice or NOP antagonist-treated mice. The nociceptive flexor responses upon intraplantar injection of bradykinin or substance P, which stimulates polymodal substance P-ergic fibers, were markedly potentiated in NOP^/ mice, compared with those in its NOP^+/+ mice. However, there were no significant changes in NOP^/ mice with adenosine triphosphate or prostaglandin I₂ agonist, which stimulates glutamatergic but not substance P-ergic fibers. The nocifensive responses induced by substance P (i.t.) were also potentiated in NOP^/ mice. On the other hand, there were no significant differences in NK1-like immunoreactivity, [³H]substance P binding, or NK1 gene expression in the dorsal horn of the spinal cord between NOP^/ and NOP^+/+ mice. In addition, NOP antagonists decreased the threshold in nociception tests driving spinal substance P neurotransmission. All these findings suggest that the N/OFQ-ergic neuron may play an in vivo inhibitory role on the second-order neurons for primary polymodal substance P-ergic fibers in the spinal cord.