Paper
Nocistatin—A New Antinociceptive Peptide
Published Mar 7, 2000 · Tat-Leang Lee, S. Tachibana
Regional Anesthesia & Pain Medicine
2
Citations
0
Influential Citations
Abstract
Nocistatin has been identified to be a neuropeptide that may play a role in the regulation of pain perception. Morphine, a major component of opium, is a potent analgesic, which has been used for many centuries for the treatment of pain. Attempts to determine its mechanism of action led to the discovery of the 3 endogenous opioid peptide families: the enkephalins, the endorphins, and the dynorphins. Subsequent research has established that these opioids activate 3 distinct classes of G-protein–coupled receptors: μ, d, and k. Recombinant DNA techniques have led to the cloning of the 3 homologous opioid receptors corresponding to each of the 3 families, and further to a novel opioid-like orphan receptor that does not bind known opioid ligands. The endogenous ligand bound to the orphan opioid receptor was recently identified as nociceptin and orphanin FQ (Noc/OFQ), a heptadecapeptide that resembles dynorphin.1,2 Noc/ OFQ is processed by proteolytic cleavage of a large precursor protein, prepronociceptin (Fig 1), which has been proposed to contain additional bioactive peptides as matured products. Okuda-Ashitaka et al.3 have recently identified another heptadecapeptide produced from bovine prepronociceptin, named nocistatin (NST), and described its interesting antagonistic activity against Noc/OFQ. Although there have been some contradictory reports, Noc/OFQ has been generally accepted to produce nociceptive effects in animals in contrast to the antinociceptive effect of other opioid peptides. Intracerebroventricular injection of Noc/OFQ produced hyperalgesia and allodynia, which are the hallmarks of neuropathic pain.1,2 Okuda-Ashitaka et al.3 showed that intrathecal administration of NST attenuated hyperalgesia and allodynia evoked by Noc/OFQ and prostaglandin E2 (PGE2), but did not affect nociceptive thresholds when injected by itself. They also found that intrathecal administration of anti-NST antibody potentiated allodynia induced by Noc/OFQ. These results indicate that although NST may regulate allodynic states caused by different mechanisms, it is not an analgesic; unlike morphine, which raises nociceptive threshold, the function of NST is to normalize nociceptive threshold. This observation is further supported by a study which showed that while intracerebroventricular administration of NST has no effect on the nociceptive threshold of control rats, it dosedependently reduced the hyperalgesia associated with carrageenan/kaolin injected in rat paws.4 Two other reports further showed that intrathecal administration of NST attenuated formalin-induced pain responses in mice and rats.5,6 Nakano et al.6 also showed that the antinociceptive effect of NST was not antagonized by naloxone, indicating that the pain-suppressive effect of NST is unrelated to the classic opioid system. NST has also been shown to reverse Noc/OFQ inhibition of glutamate release from rat brain slices7 and the antimorphine effect of Noc/OFQ in rat brain.8 Taken together, these findings strongly suggest that Noc/OFQ and NTS, which are derived from the same precusor, are involved in the pain regulation system at the supraspinal and spinal level. NST and Noc/OFQ have been shown to colocalize in the superficial laminae of the mouse spinal cord,3 as expected for products from the same gene, a distribution consistent with their potential roles in modulating spinal pain pathways. However, the identity of the NST receptor is not yet established, although NST has been shown to bind a receptor that is distinct from that of Noc/OFQ.3 Andoh et al.9 reported a remarkable increase in the Noc/OFQ gene expression in the dorsal root ganglion (DRG) of rats injected with carrageenan. Because the prepronociceptin mRNA is not detected in the DRG of From the Departments of Anaesthesia (T.-L.L.) and Biological Sciences (S.T.), National University of Singapore, Singapore. Accepted for publication March 7, 2000. Reprint requests: Tat-Leang Lee, M.B.B.S., M.Med. (Aneas), F.A.N.Z.C.A., Department of Anaesthesia, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074. E-mail: analeetl@nus.edu.sg r 2000 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/00/2504-0015$5.00/0 doi: 10.1053/rapm.2000.7623
Nocistatin (NST) is a neuropeptide that normalizes pain perception, but it does not act as an analgesic, unlike morphine, which raises nociceptive threshold.
Full text analysis coming soon...