[Molecular pharmacology and physiology of nociceptin].
The family of the G protein-coupled opioid receptors was recently extended by a novel member that did not bind any of the typical opioid receptor ligands. Identification of the orphan receptor in this way led to the advent of "reverse pharmacology" to identify the corresponding physiological ligands. Nociceptin, a heptadecapeptide, which was discovered as an endogenous ligand, first, attracted us by its reported nociceptive or anti-opioid actions. However, following studies revealed that this peptide has both nociceptive and antinociceptive actions under different conditions; e.g., administration routes or doses affect its actions. In our recent studies using a unique peripheral peripheral nociception test, nociceptin given locally at lower doses was found to produce nociception through substance P release from nociceptor endings, while at higher doses, it produced antinociceptive actions through an inhibition of phospholipase C activity stimulated by nociceptive substances. Such hypothetical mechanisms can be applied to the mechanisms of nociceptin-induced paradoxical actions in the central nervous system. The physiological role of nociceptin has recently been reported using nociceptin receptor knock-out mice. Following the report of a hearing problem in such mice, the nociceptin receptor was found to be involved in the development of morphine analgesic tolerance. In this review, more findings on the physiological roles of nociceptin or its receptor, such as pain control and memory-learning, are discussed on the basis of reports using nociceptin receptor knock-out mice.
Ueda
H
H
Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Japan.
Inoue
M
M
D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D018847:Opioid Peptides / Q000494:pharmacology* / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D011957:Receptors, Opioid / Q000819:agonists*; D000097629:Nociceptin
D018847:Opioid Peptides; D011957:Receptors, Opioid; D000097629:Nociceptin