Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more

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Abstract

The publication of the δ opioid receptor sequence led to the cloning of three homologous receptors: the μ and κ opioid receptors, and a novel opioid-like orphan receptor.  The orphan receptor's endogenous ligand, a 17-amino-acid peptide that resembles dynorphin, was named `orphanin FQ' and `nociceptin' (OFQ/N1–17). The OFQ/N1–17 receptor is expressed widely in the nervous system, and it is becoming clear that the peptide is likely to participate in a broad range of physiological and behavioral functions. At the cellular level, OFQ/N1–17 has much in common with the classical opioids; however, functional studies are now revealing distinct actions of this peptide. Identified only two years ago, OFQ/N1–17 has already attracted a great deal of attention.  The number and diversity of papers focused on OFQ/N1–17 at the recent meeting of the Society for Neuroscience augur an exciting future for this new peptide.

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.

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