Trends in Neurosciences
Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more
Section snippets
The endogenous ligand for the opioid-like orphan receptor: orphanin FQ/nociceptin1–17
At the 1995 meeting of the International Narcotics Research Conference in St Andrews, Scotland, J.C. Meunier reported the isolation of a 17-amino acid peptide from rat brain that decreased forskolin-stimulated cAMP production in vitro. A paper terming this peptide `nociceptin' was subsequently published by Meunier et al.[9] A peptide of identical sequence, isolated from pig brain, was reported simultaneously by Reinscheid et al.[10] who named it orphanin FQ (OFQ; Fig. 1)11, 12. For the purposes
Orphanin FQ/nociceptin1–17 is encoded within a precursor protein
A full-length cDNA that encodes the OFQ/N1–17 peptide as part of a larger protein, preproOFQ/N (ppOFQ/N), has been identified12, 17. Its gene (gene symbol PNOC) maps to human chromosome 8p21 ([12]). Dibasic amino acids, recognition sites for several endopeptidases[18], flank the OFQ/N1–17 sequence, which is consistent with the idea that ppOFQ/N is proteolytically processed. Interestingly, there are several paired dibasic amino acids distributed throughout ppOFQ/N, which suggests that this
Cellular actions of OFQ/N1–17
The ability to activate the OFQ/N receptor has significantly advanced our understanding of its cellular physiology. In addition to the initial reports that activation of the receptor inhibits cAMP production, several studies have now documented an activation of inwardly rectifying K+ channels expressed in Xenopus oocytes[21] as well as in all brain regions tested to date, including the dorsal raphé[22], locus coeruleus[23], arcuate nucleus of the hypothalamus[24], and the periaqueductal gray
Functional studies of OFQ/N1–17: anatomy and behavior
When confronted with what might be a new neurotransmitter, the major challenge is to understand the various roles that the substance plays in the organism. In the first two studies to address this issue, Reinscheid et al.[10] and Meunier et al.[9] used an intracerebroventricular (i.c.v.) route of administration and found that at high doses, OFQ/N1–17 impaired locomotion and affected nociceptive sensitivity in mice.
The i.c.v. approach continues to be widely used to identify behaviors in which
Development of OFQ/N receptor agonists and antagonists
Although a great deal has been learned about the OFQ/N1–17 system in the two years since its discovery, the need for additional compounds, agonists as well as antagonists, with selectivity for the OFQ/N1–17 receptor cannot be overemphasized. Confidence in all of the studies published to date will be greatly increased once it can be demonstrated that a particular effect of OFQ/N1–17 can be antagonized pharmacologically. Some progress in this direction was recently reported by Dooley and Houghten
Concluding remarks and future directions
At the cellular level, the actions of OFQ/N1–17 have much in common with those of the opioid peptides: the activated receptor is coupled to inhibition of adenylyl cyclase, and the peptide has been shown to hyperpolarize neurons in a number of brain regions. As with the opioids, OFQ/N1–17 might also modulate neurotransmitter release through its actions on N-type voltage-gated Ca2+ channels. Unfortunately, our understanding of how these actions of OFQ/N1–17, at the level of the cell membrane, are
Acknowledgements
Supported in part by the Markey Charitable Trust (DKG) and NIDA (DKG and MMH). Special thanks to J. Mogil and J. Grisel for many thoughtful discussions and all those who shared their unpublished data with us. We would also like to thank J. Shiigi and E. Wiltshire for their help in preparing the illustrations.
References (75)
- et al.
Life Sci.
(1986) FEBS Lett.
(1994)FEBS Lett.
(1994)- et al.
Trends Pharmacol. Sci.
(1997) J. Biol. Chem.
(1996)Eur. J. Pharmacol.
(1997)J. Biol. Chem.
(1996)Peptides
(1998)J. Biol. Chem.
(1996)Trends Neurosci.
(1995)
Biochem. Biophys. Res. Commun.
Neuroscience
Eur. J. Pharmacol.
Neurosci. Lett.
Neurosci. Lett.
Neuroscience
Neuroscience
Neurosci. Lett.
Neurosci. Lett.
Neuroscience
Brain Res.
Neurosci. Lett.
Brain Res.
FEBS Lett.
Neuroscience
Eur. J. Pharmacol.
Eur. J. Pharmacol.
Eur. J. Pharmacol.
Science
Proc. Natl. Acad. Sci. U. S. A.
Biochem. J.
Proc. Natl. Acad. Sci. U. S. A.
Nature
Science
Nature
Proc. Natl. Acad. Sci. U. S. A.
J. Med. Chem.
Cited by (285)
Selective alterations in endogenous opioid system genes expression in rats selected for high ethanol intake during adolescence
2020, Drug and Alcohol DependenceThe Complex Role of Nociceptin Signaling in Stress: Clarity Through Neuroimaging?
2020, Biological Psychiatry5.35 - Forebrain Opiates
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second EditionEnvironmental stressors and alcoholism development: Focus on molecular targets and their epigenetic regulation
2019, Neuroscience and Biobehavioral ReviewsSingle-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease
2018, American Journal of Human Genetics