The Nociceptin/Orphanin FQ Receptor (NOP) as a Target for Drug Abuse Medications

The Nociceptin Receptor (NOP) and its Ligand, Nociceptin/Orphanin FQ (N/OFQ)

The NOP receptor, previously called the opioid receptor-like receptor (ORL1, XOR1 and LC132) was discovered in 1994, belongs to the opioid receptor family and has nucleotide and amino acid homology to the three opioid receptors comparable to that which they have with each other [2–4]. However, when NOP is transfected into mammalian cells, it does not bind opiates with high affinity as would be expected for an opioid receptor. The endogenous 17-amino acid peptide ligand for NOP was discovered simultaneously by two groups in 1995 and was named nociceptin [5] or orphaninFQ (N/OFQ) [6] respectively. Although N/OFQ closely resembles dynorphin, the endogenous kappa opioid receptor ligand, N/OFQ has almost no affinity for mu-, delta-, and kappa-opioid receptors [7] and its pharmacological effects are not reversed by the universal opioid antagonist, naloxone [8].

Being in the opioid receptor family, NOP and N/OFQ have been extensively evaluated for their roles in nociceptive pathways and anti-nociceptive effects. Functionally, the N/OFQ peptide is considered to have an ‘anti-opioid’ action. When injected intracerebroventricularly (i.c.v), N/OFQ antagonizes opioid analgesia, including opioid-mediated stress-induced analgesia from the i.c.v procedure [9]. Icv N/OFQ also antagonizes the analgesic effects of mu, delta and kappa agonists [10]. In contrast, spinal administration of N/OFQ produces a opioid-like, anti-nociceptive effect. It is still not clear from studies using systemically administered NOP small-molecule ligands whether NOP agonists or antagonists, by themselves, have any value in pain therapy. Excellent reviews on this subject have been published [11–13]. The NOP receptor and N/OFQ are also actively being investigated as targets for anxiolytic medications. N/OFQ was shown to have potent anxiolytic activity in rodent models of stress, after i.c.v infusion [14, 15]. The small-molecule NOP receptor agonist, Ro 64-6198 Fig. (1) has also been shown to have anxiolytic activity in several rodent models of anxiety [16, 17]. Recently, a newer NOP agonist, SCH 221510 (Fig. 1) reported by Schering Plough, was characterized in various models of anxiety, and shown to have potent anxiolytic effects that compared well with a known benzodiazepine, chlordiazepoxide [18]. While the mechanism of its anxiolytic activity is not completely understood, N/OFQ was recently shown to act as a functional CRF antagonist, and to reverse behavioral effects of stress, including anorexia [19, 20] and stress-induced reinstatement of alcohol-seeking behavior in rats [21]. N/OFQ’s inhibition of stress-related responses may provide an advantage, in addition to its functional anti-opioid activity, for the treatment of drug abuse and relapse. Opioid antagonists like naltrexone are clinically used for treatment of alcohol and opioid addiction, but have drawbacks such as anxiogenic activity and withdrawal symptoms. NOP receptor agonists, on the other hand, have been shown to block the rewarding effects of cocaine, morphine, amphetamines and alcohol (see below), and with their anxiolytic profile, may also be useful in the treatment of drug relapse. The role of the NOP receptor in reward and stress pathways suggests that the NOP-targeted agonist ligands may possess a therapeutically beneficial profile for drug abuse treatment.

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Fig. 1

Structures of selective NOP agonist ligands with characterized pharmacology

N/OFQ Pharmacology in Reward and Motivation Pathways

Several studies with the natural ligand N/OFQ and NOP receptor knockout mice provide compelling evidence that the N/OFQ-NOP receptor system plays a significant role in the reward process and drug abuse in particular. There is a moderate to high density of NOP receptors in areas implicated in drug abuse and reward, including the nucleus accumbens, ventral tegmental area, medial prefrontal cortex, lateral hypothalamus, amygdala, and the bed nucleus of stria terminalis [22, 23]. Furthermore, i.c.v. administration of N/OFQ suppresses basal and drug-stimulated dopamine release in the nucleus accumbens [24–27]. Consistent with its inhibition of dopamine release, N/OFQ has been shown to block the rewarding properties of several common drugs of abuse. In particular, N/OFQ was shown to block acquisition of conditioned place preference (CPP) (an animal model to assess modulation of drug-induced reward), induced by morphine [28, 29], cocaine [30, 31], amphetamines [32, 33], and alcohol [34, 35].

N/OFQ has been particularly well examined in animal models of alcohol addiction and relapse. Not only does it block acquisition and expression of ethanol-induced CPP in mice, N/OFQ, administered i.c.v., also blocks reinstatement of extinguished alcohol CPP [35], a model of drug-induced relapse. Elegant studies carried out by Ciccocioppo and colleagues in alcohol-preferring Marchigian Sardinian (msP) rats [36] suggest that dysregulation of the NOP-N/OFQ system may be a pathophysiological consequence of alcohol addiction in these rats [37]. In these genetically selected alcohol-preferring rats, i.c.v. administration of N/OFQ daily for 6 days, reduced alcohol self-administration. N/OFQ also significantly inhibited the reinstatement of extinguished alcohol responding in these rats [38]. Recent detailed studies by these same researchers appear to suggest that the anti-CRF anti-stress activity of N/OFQ may play a role in reducing alcohol drinking in these msP rats, which are highly sensitive to stress and show an anxious phenotype [37]. Similar reductions in alcohol intake were also observed with 6-day administration of peptidic NOP agonists UFP-102 and UFP-112 (discussed below) [39, 40]. These results clearly suggest that the NOP-N/OFQ system is implicated in alcohol addiction and that NOP receptor agonists may be a promising class of treatment agents for alcohol abuse.

The overall inhibitory effect of N/OFQ on neurotransmitter release may underlie its ability to decrease rewarding effects of drugs of abuse. NOP receptor activation by exogenously administered N/OFQ decreases basal [41] as well as morphine- [24, 25] and cocaine-induced [42] dopamine release from mesolimbic areas in rodent models. NOP receptors are present on greater than 80% of the dopamine-containing cells in the VTA [43]. N/OFQ acting on presynaptic NOP receptors in the central amygdala was shown to decrease ethanol-induced GABA release and GABAergic neurotransmission, opposing the effect of ethanol [44]. Several studies now show that enhanced GABAergic transmission in the central amygdala (CeA) is significantly involved in alcohol reward and dependence [45, 46]. These results with N/OFQ are consistent with observations in the alcohol-preferring msP rats, and further corroborate the suggestion that NOP receptor agonists may be particularly useful for treatment of alcohol addiction.

Although most studies have examined the effect of exogenously administered N/OFQ in reward pathways, it appears that the endogenous N/OFQ tone suppresses increases in basal stimulation of reward pathways and may play a role in the acquisition of addiction. Indeed, NOP receptor knockout mice show a stronger METH-, ethanol- and cocaine-induced CPP [47, 48]. However, N/OFQ was not successful in blocking self-administration of heroin [49]. Further studies are clearly needed to study the role of N/OFQ in the various aspects of the drug addiction process, but taken together, all these studies confirm the involvement of NOP receptors in drug addiction and suggest the utility of NOP agonists as drug abuse medications.

Anti-Rewarding Effects of Small-Molecule and Peptidic NOP Ligands

The only synthetic small-molecule NOP agonist studied in reward-related behavioral assays is Ro 64-6198 Fig. (1), which was among the first, highly selective NOP agonists reported [16, 50, 51]. A small study reported by Kotlinska et al. [52] first reported that Ro 64-6198, administered intraperitoneally (i.p.) did not affect the development of morphine dependence when given during the acquisition phase. Ro 64-6198 however, decreased the withdrawal symptoms when administered prior to naloxone, to morphine-dependent mice. This activity was attributed to the decrease in locomotor/rotarod activity observed with Ro 64-6198 at the 1 mg/kg and 3 mg/kg doses used. However, in a later detailed study, Shoblock et al. [53] reported that Ro 64-6198 blocked the acquisition and reinstatement but not the expression, of morphine CPP in mice. They did not observe any decrease in locomotor activity at doses of 0.1 to 1 mg/kg of Ro 64-6198. Surprisingly, Kuzmin et al. reported that Ro 64-6198 blocks the expression as well as the acquisition and reinstatement of alcohol CPP in mice [35]. Although a decrease in locomotor activity was observed at the 1 mg/kg dose of Ro 64-6198, tolerance quickly developed to this effect after three injections [35]. It appears that the effect on locomotion may be dependent on the mouse strain used. Ro 64-6198 was also reported to reduce alcohol self-adminstration and reduce relapse-like alcohol drinking in Wistar rats, when administered i.p. at doses upto 1 mg/kg [54]. Interestingly, however, when administered to the alcohol-preferring msP rats, Cicco-cioppo et al. observed that Ro 64-6198, at 1 mg/kg administered i.p., actually increased alcohol consumption [55]. Although this increase in alcohol consumption in msP rats was attributed to a residual mu opioid agonist activity of Ro 64-6198 and was inhibited by naloxone, no such mu-related effects have been reported in any previous studies with Ro 64-6198 at various doses in rats and mice [56]. This effect in msP rats may be specific in this genetically selected rat strain and requires further clarification. Clearly, more studies with other small-molecule NOP agonists are needed to understand the NOP-N/OFQ system in alcohol addiction.

Although several highly selective peptidic NOP receptor ligands have been developed [57], only a handful of them have been examined in only one study in the alcohol-preferring msP rats [55]. Peptides UFP-102, UFP-112 [39, 40] and OS-462, a peptide NOP ligand reported by Nippon Shinyaku [58], when administered i.c.v., were shown to decrease alcohol drinking in msP rats, with no effect on food or water intake. Other than N/OFQ itself, NOP peptide ligands have not been examined against other drugs of abuse.

Support by a grant from NIDA (DA 14026, N.Z.) is gratefully acknowledged. The author would like to thank her colleagues, Lawrence Toll, Taline Khroyan, Faming Jiang, Cris Olsen, and Willma Polgar for helpful discussions.