In vivo pain-inhibitory role of nociceptin/orphanin FQ in spinal cord

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.