Elsevier

Peptides

Volume 21, Issue 7, July 2000, Pages 907-917
Peptides

Regular paper
Tissue distribution of the opioid receptor-like (ORL1) receptor

https://doi.org/10.1016/S0196-9781(00)00227-8Get rights and content

Abstract

The ORL1 receptor is a G protein-coupled receptor structurally related to the opioid receptors, whose endogenous ligand is the heptadecapeptide nociceptin/orphanin FQ. In this review, data which have contributed to the mapping of the anatomic distribution of the ORL1 receptor have been collated with an emphasis on their relation to physiological functions. The ORL1 receptor is widely expressed in the central nervous system, in particular in the forebrain (cortical areas, olfactory regions, limbic structures, thalamus), throughout the brainstem (central periaqueductal gray, substantia nigra, several sensory and motor nuclei), and in both the dorsal and ventral horns of the spinal cord. Regions almost devoid of ORL1 receptors are the caudate-putamen and the cerebellum. ORL1 mRNA and binding sites exhibit approximately the same distribution pattern, indicating that the ORL1 receptor is located on local neuronal circuits. The ORL1 receptor is also expressed at the periphery in smooth muscles, peripheral ganglia, and the immune system. The anatomic distribution of ORL1 receptor suggests a broad spectrum of action for the nociceptin/orphanin FQ system (sensory perception, memory process, emotional behavior, etc.).

Introduction

Using molecular screening methods based on opioid receptor gene sequences, an orphan G protein-coupled receptor was identified by several groups in human [50], murine [3], [9], [23], [41], [60], [83], [85], and porcine [64] species. It has been referred to as ORL1 (for Opioid Receptor-Like) receptor because, although it shares a high sequence similarity with the μ-, δ-, and κ-opioid receptors, it does not bind opioid ligands.

At the cellular level, the ORL1 receptor is coupled, as are the opioid receptors, to Gi/Go-protein mediated transduction systems: inhibition of adenylate cyclase, activation of an inwardly rectifying K+ conductance, and inhibition of voltage-sensitive Ca2+ channels. These intracellular effects contribute to inhibit the release of several neurotransmitters and, therefore, confer a neuromodulatory function on the ORL1 receptor (for review, see refs. [34], [47] and this issue).

The endogenous ligand of the ORL1 receptor has been purified from rat [48], porcine [68], and bovine [62] brain by monitoring adenylate cyclase inhibition in ORL1-transfected cells. It was named both nociceptin, because of its apparent pronociceptive properties [48], and orphanin FQ [68]. As a classic neuropeptide, nociceptin/orphanin FQ is present as a single copy flanked by basic proteolytic cleavage sites, in a larger, highly conserved, precursor [48], [51], [61], [70]. Nociceptin/orphanin FQ is a heptadecapeptide (Phe-Gly Gly-Phe-Thr-Gly Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) with N-terminal tetrapeptide reminiscent to that of the opioid peptides. Moreover, its basic core is similar to that of the κ-opioid receptor endogenous ligand, dynorphin. However, nociceptin/orphanin FQ binds to the ORL1 receptor with high affinity (Kd ≃ 0.1 nM) and interacts poorly with the opioid receptors, in part because of the presence of a phenylalanine residue at position 1 of the peptide in place of the tyrosine of opioid peptides [4], [34], [47], [68]. Furthermore, in vitro and in vivo effects induced by nociceptin/orphanin FQ are not reversed by the opioid antagonist naloxone. To date, the only peptide reported to behave as an antagonist at the ORL1 receptor, the analog [Phe1ψ(CH2-NH)Gly2]nociceptin-(1–13)-NH2 [29], has however also been shown to have agonist properties both in vitro [5] and in vivo [27], [87].

The identification of the endogenous ligand of the ORL1 receptor has been an important step assisting in the characterization of the physiological properties of the ORL1 receptor. Most of the behavioral studies in the central nervous system have focused on pain perception because of the analogy between the ORL1 and opioid receptors (for review, see refs. [13], [34], [47] and this issue). While many findings are sometimes contradictory, it is clear that the supraspinal action of nociceptin/orphanin FQ on nociperception is not opioid-like [13]. Hyperalgesia has been observed in various pain tests following central injection of the peptide [7], [48], [59], [68], [92]. However, this effect was suspected to be due to a reversal of the analgesia induced by the stress of the intracerebroventricular (i.c.v.) injection itself [49]. Moreover, nociceptin/orphanin FQ has been shown to behave as a supraspinal functional anti-opioid peptide [28], [49], [79], [92]. In contrast, spinal administration of nociceptin/orphanin FQ in the rat can induce, as opiates do, a strong analgesia [18], [79], [88], [89] and, even potentiates morphine antinociception [79]. In addition, both stimulatory [21] and inhibitory [15], [59], [68] effects of nociceptin/orphanin FQ on motricity have been observed in mouse and rat. Furthermore, nociceptin/orphanin FQ has been implicated in memory processes [44], [45], [71], feeding, and hormonal regulation [47]. The peptide possesses also anxiolytic properties [36]. In the periphery, nociceptin/orphanin FQ inhibits the contraction of various isolated organs [6], [19], [25], [30], [65] and has been described as having vasodilatatory [8] and diuretic/antinatriuretic [38] properties in rat.

One means to obtain an insight into the complexity of the pharmacological actions of nociceptin/orphanin FQ, and to identify new physiological activities, is to analyze the tissue distribution of the peptide and its receptor. This review is a compilation of the various studies that have shown the ORL1 receptor to be widely expressed in the brain and spinal cord, a number of peripheral organs (intestine, vas deferens, arteries), and the immune system.

Section snippets

Anatomical distribution of the ORL1 receptor

Before the endogenous ligand of the ORL1 receptor was identified, the distribution of ORL1 transcripts in murine tissues was investigated by in situ hybridization studies [3], [23], [41], [50], [85] and Northern [9] and RT-PCR [83] analyses. Immunolocalization of the receptor protein, using a monoclonal antibody raised against the N-terminal extracellular domain of the rat ORL1 receptor, provided a detailed mapping of the rat brain [2] and spinal cord [52]. Following the identification of

Distribution in relation to aminergic system

As illustrated in Fig. 1, it is of note that the ORL1 receptor is located in nearly all nuclear groups of the diffuse modulatory system, i.e. adrenergic/noradrenergic, cholinergic, dopaminergic, and serotoninergic nuclei. It may therefore be involved in the modulation of amine release in the brain, and thus influence many important physiological functions.

Conclusion

Anatomic data reveal that the ORL1 receptor is widely expressed in the brain, spinal cord, and peripheral nervous system. It is not present in brain structures associated with a single physiological function or neurotransmitter system, but is found in areas involved in various processes, among them, pain and sensory perception, memory, stress, motricity, hormonal regulation. This widespread distribution could reflect the association of the ORL1 receptor with a large number of physiological

Acknowledgements

We thank Drs J. M. Zajac, M. Roumy, S. Schiffmann, and J. C. Meunier for critical review of the manuscript and Dr C. Topham for language correction. C.M. is supported by the Centre National de la Recherche Scientifique and L.M. is supported by the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche.

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