Pain transmission regulated by novel neuropeptides nocistatin and nociceptin/orphanin FQ

Received December 30, 2001 A neuropeptide nociceptin or orphanin FQ (Noc/OFQ) was previously identified as an endogenous ligand for the orphan opioid receptor-like receptor. Studies on the analysis of the precursor of Noc/OFQ, we identified another novel neuropeptide and named it “nocistatin”. Noc/OFQ is involved in a broad range of pharmacological actions in various tissues from the central nervous system to the periphery. We found that intrathecal administration of Noc/OFQ induced pain responses including touch-evoked pain (allodynia) and thermal hyperalgesia. While both the allodynia and the hyperalgesia evoked by Noc/OFQ were transmitted by capsaicin-sensitive primary afferent fibers and initially in the disinhibition of the inhibitory glycinergic response, the allodynia was mediated by glutamate through the N-methyl-D-asparateate receptor comprising the GluRε1 subunit and the thermal hyperalgesia was mediated by substance P. Two bioactive peptides, Noc/OFQ and nocistatin exist the same precursor prepronociceptin/orphanin FQ. Simultaneous administration of nocistatin blocked the allodynia and thermal hyperalgesia induced by Noc/OFQ, and anti-nocistatin antibody decreased the threshold for the Noc/OFQ-induced allodynia. The carboxy-terminal hexapeptide of nocistatin (Glu-Gln-Lys-Gln-Leu-Gln), which is conserved in bovine, human and murine species, possesses the blocking activity. Nocistatin also attenuated the allodynia and thermal hyperalgesia evoked by prostaglandin E2 and the inflammatory pain induced by formalin or carrageenan/kaolin, and reversed morphine tolerance and the Noc/OFQ-induced inhibition of morphine analgesia. Nocistatin and Noc/OFQ are novel bioactive peptides produced from the same precursor, and they play opposite roles in the regulation of pain transmission.