Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats

Abstract

The effects induced by nociceptin on morphine-induced release of dopamine (DA), 3,4-dihydroxyphenilacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and nucleus caudate were studied in rats by microdialysis with electrochemical detection. Nociceptin administered intracerebroventricularly (i.c.v.) at doses of 2, 5 and 10 nmol/rat changed neither DA nor metabolites release in the shell of the nucleus accumbens or in the nucleus caudate. Morphine administered intraperitoneally (i.p.) (2, 5, and 10 mg/kg) increased DA and metabolites release more in the shell of the nucleus accumbens than in the nucleus caudate. When nociceptin (5 or 10 nmol) was administered 15 min before morphine (5 or 10 mg/kg), it significantly reduced morphine-induced DA and metabolites release in the shell of the nucleus accumbens, whereas only a slight, nonsignificant reduction was observed in the nucleus caudate. Our data indicate that nociceptin may regulate the stimulating action associated with morphine-induced DA release more in the nucleus accumbens than in the nucleus caudate, and are consistent with recent observations that nociceptin reversed ethanol- and morphine-induced conditioned place preference. Therefore, the nociceptin-induced reduction of DA release stimulated by morphine in the nucleus accumbens, and the results obtained with nociceptin in the conditioned place preference procedure suggest a role for nociceptin in the modulation of the behavioral and neurochemical effects of abuse drugs.

Introduction

Considerable evidence indicates that opioids can modulate the activity of the nigrostriatal and mesolimbic dopamine neurons [47]. It has been proposed that this activity underlies the motivational and locomotor effects of these drugs as well as the development of various aspects of opiate dependence [17]. The nigrostriatal pathway consists of dopaminergic cell bodies in the substantia nigra and ascending axons that terminate throughout the striatum, morphologically divided into caudate-putamen, nucleus accumbens (shell and core) and olfactory tubercle. Opioid administration has been reported to cause an increase in dopamine (DA) release in the nucleus caudate as measured by microdialysis [9], [12]. The mesolimbic pathway projecting from the ventral tegmental area to the nucleus accumbens is also potently modulated by opioids, which alter accumbens DA metabolism as well when systemically or intracerebroventricularly (i.c.v.) administered [9], [40a], [41b], [48].

A new member of the opioid peptide family has been recently isolated. This heptadecapeptide named orphanin FQ or nociceptin is an endogenous agonist for the opioid receptor-like 1 (ORL1) receptor [26], [37]. Although nociceptin is structurally similar to opioid peptides (endorphins, enkephalins, and dynorphins), it seems to be pharmacologically distinct from opioids. In binding and biologic assays, nociceptin does not interact with μ, δ, or κ opioid receptors [26], [37], whereas at the cellular level, the effects it induces are characteristic of those evoked by opioids [43]. In CHO cells transfected with the ORL1 receptor, nociceptin inhibits forskolin-stimulated adenylate cyclase activity [26], [37]. Furthermore, nociceptin inhibits Ca²⁺ entry in cultured SH-SY5Y cells [6] and in hippocampal neurons [22], and activates K⁺ conductance in locus coeruleus, dorsal raphe, and periacqueductal gray neurons [7b], [44], [45].

Nociceptin derives from a larger precursor known as preproorphanin FQ or prepronociceptin (ppNOC) whose gene is transcribed predominantly in the central nervous system (CNS). The wide distribution of the nociceptin precursor and its ORL1 receptor in the CNS [1], [3] suggests that nociceptin is potentially involved in numerous physiological functions [16]. Indeed, nociceptin administration depresses the cardiovascular function [4], inhibits neurogenic inflammation [15], increases food intake [36], inhibits long-term potentiation [49], impairs spatial learning [38], and exhibits anxiolytic properties [19]. Furthermore, this peptide has been shown to be primarily implicated in pain perception. In contrast to the classic analgesic opioid effects, it elicits hyperalgesia or allodynia when administered i.c.v. or intrathecally (i.t.) in mice [26], [33]. Hence, the name “nociceptin” in accordance with its apparent pronociceptive properties. Moreover, it has been reported that central administration of nociceptin antagonizes opioid-mediated stress-induced analgesia and μ-, δ-, and κ-receptor-mediated analgesia in mice [27a], [28b].

In a previous paper [11] we reported that nociceptin reduced morphine-induced DA and metabolites release from the nucleus accumbens. To confirm and extend this finding, we investigated: 1) whether nociceptin administered at low doses was able to modify DA release in the shell of the nucleus accumbens and in the nucleus caudate, and 2) whether nociceptin was able to interfere with morphine-stimulated DA and metabolites release in the shell of the nucleus accumbens and in the nucleus caudate, by using microdialysis in freely moving rats.