Regular paperNociceptin/orphanin FQ and drugs of abuse
Introduction
Nociceptin/orphanin FQ (NC), the endogenous ligand of the opioid receptor-like1 (ORL1) receptor, is a 17-amino acid neuropeptide, structurally related to the opioid peptide dynorphin A [60], [74], [88], [89]. Despite its structural homology with opioid peptides, NC does not bind to μ, δ, and κ opioid receptors, nor do opioid peptides activate the ORL1 receptor [87]. Activation of membrane ORL1 receptors by NC results in the same sequence of intracellular events induced by opioid receptors, namely negative coupling with adenylyl cyclase, activation of inwardly rectifying K+ channels, and inhibition of Ca2+ current in a pertussis toxin-sensitive manner [18], [32], [59], [60], [89]. However, these cellular responses to NC are insensitive to naloxone [18], [32], confirming that the pharmacological actions of this peptide are not mediated by the classic opioid receptors. Detailed structure analysis revealed important differences between ORL1 and μ, δ, and κ opioid receptors [74], [87], [88], suggesting that separate mutations might have led to a coordinated pharmacological separation of the NC system from the opioid system [58], [88]. This view is supported by brain mapping studies showing that the neuroanatomical distribution of NC and its receptor differs from that of opioid peptides and opioid receptors [4], [18], [25], [36], [70], [98].
NC has been reported to block opioid-induced supraspinal analgesia, and it has been proposed that it may act as a functional antiopioid peptide in the control of brain nociceptive processes [63], [65], [73].
It is well known that the endogenous opioid system also plays a major role in mediating the rewarding and reinforcing actions of opiates and other abused drugs [33], [34], [102], [103]. Thus, several studies have recently evaluated whether NC behaves as a functional antiopioid peptide in relation to the motivational properties of opiates and ethanol as well. The aim of the present article is to review these studies and to discuss new directions for future research about the effects of NC on drug abuse.
Section snippets
The brain reward system
More than 40 years ago, Olds and Milner discovered that direct electrical stimulation of different brain areas can be rewarding and act as a reinforcer [75]. Afterwards, a large number of studies using electrophysiological techniques, microdialysis, electrical self-stimulation and drug self-administration, have been conducted to identify the neuroanatomical and neurochemical pathways of the “brain reward system” [46], [113].
The medial forebrain bundle, connecting the olfactory tubercle (OT),
Nociceptin/orphanin FQ and ethanol intake in alcohol-preferring rats
A study of our group has shown that ICV treatment with a dose as low as 500 ng/rat of NC significantly modifies ethanol consumption in genetically selected Marchigian Sardinian (msP) alcohol-preferring rats [16]. In a 7-day subchronic treatment, NC attenuated alcohol drinking in freely feeding and drinking msP rats, which were offered 10% ethanol 30 min/day, at the beginning of the dark phase of the light cycle. The intake of 10% ethanol became significantly lower than that of controls after 3
Nociceptin/orphanin FQ and the rewarding properties of morphine
NC was first indicated as an antiopioid peptide for its property to reverse morphine-induced analgesia [63], [64]. However, a recent study by Murphy et al. [66], as well as work simultaneously carried out in our laboratory [3] suggests that the antiopioid action of NC also extends to the motivational properties of morphine.
Murphy and co-workers reported that ICV administration of NC at doses of 5000–20000 ng/rat blocked CPP induced by subcutaneous (s.c.) injections of 3 mg/kg of morphine.
In our
Nociceptin/orphanin FQ and psychostimulants
At present, no study has been published on the effect of NC on the rewarding effects of psychostimulants.
It has been reported that NC does not alter locomotor sensitization induced by cocaine [69]. This finding, together with the observation that NC fails to inhibit locomotor sensitization induced by morphine, supports the idea that NC does not interfere with the process of sensitization to drugs of abuse.
Nociceptin/orphanin FQ versus opioid antagonists
Opioid receptor antagonists represent important pharmacological tools to treat abstinent individuals with a history of opiate abuse and dependence. The long acting drug, naltrexone, has been approved by the Food and Drug Administration for the treatment of alcohol dependence. However, a relevant clinical problem with opioid receptor antagonists is low compliance, probably related to the aversive properties of these drugs [47], [86], [108]. In laboratory animals, place and taste aversion have
Conclusions
NC was isolated only a few years ago, and promptly attracted the attention of many researchers, mainly for its effects on nociceptive processes. However, increasing evidence suggests that this peptide may also play a crucial role in the regulation of reward mechanisms and drug abuse processes.
The data discussed in this review indicate that NC behaves as a functional antiopioid peptide in regard to the motivational properties of opiates and ethanol. Indeed, low ICV doses of NC (500–1000 ng/rat)
Acknowledgements
This study was supported by grant from the University of Camerino and MURST (Cofin99). The authors thank Sheila Beatty for linguistic revision of this article.
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