The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models

Abstract

RationaleAlcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.ObjectivesHere, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.ResultsSR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced (“hangover”) anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.ConclusionThese findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

Influence of stress associated with chronic alcohol exposure on drinking

“…For example, infusion of nociceptin into brain ventricles reduced alcohol conditioned reward as well as relapse-like behavior provoked by either stress or alcohol-related cues (Ciccocioppo et al, 2004; Martin-Fardon et al, 2000). Likewise, systemic administration of brain-penetrant nociception analogues reduced alcohol self-administration (Aziz et al, 2016; Ciccocioppo et al, 2014; Kuzmin et al, 2007). Direct injection of nociceptin into the CeA also was reported to reduce alcohol consumption (Economidou et al, 2008).…”

“…This effect may be mediated by nociception interacting with alcohol-induced modulation of GABA and glutamate transmission in the CeA (Kallupi et al, 2014a; Kallupi et al, 2014b). Additionally, chronic alcohol exposure appears to enhance sensitivity to NOP activation, as nociceptin (or its analogues) were shown to be more effective as anxiolytics and reducing elevated drinking associated with dependence (Aujla et al, 2013; Aziz et al, 2016; de Guglielmo et al, 2015; Economidou et al, 2011; Martin-Fardon et al, 2010). …”

Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys

“…Beyond their role in analgesia, in part because the NOP peptide can inhibit the beta-endorphin neurons that may mediate alcohol abuse [64,65], NOP receptors have been investigated in rodent models of AUD. These studies have consistently demonstrated that stimulating NOP receptors can decrease the abuse-related effects of ethanol [22][23][24][25][26][27][28][29][30]. The present studies compared the effects of the MOP receptor agonist buprenorphine and the bifunctional MOP/NOP agonist BU08028 in rhesus monkeys who had free access to a 4% ethanol solution 6 h per day, 5 days per week.…”

“…For example, NOP receptor agonists can decrease neurochemical and neurophysiological effects of ethanol in rats [20,21]. Moreover, administration of the NOP peptide or NOP receptor agonists can attenuate behavioral effects of ethanol in rodent models, including ethanol self-administration, ethanol seeking, and symptoms of ethanol withdrawal [22][23][24][25][26][27][28][29][30]. More recently, it was reported that antagonism or genetic deletion of NOP receptors also decreased ethanol drinking [31,32], and that a NOP receptor antagonist reduced heavy drinking in a clinical trial [33].…”

Anti-stress neuropharmacological mechanisms and targets for addiction treatment: A translational framework

“…The latter findings suggest a history of alcohol dependence dysregulates the nociceptin system, which can be reversed with NOP agonist treatment. A different small-molecule NOP agonist, SR-8993, blocked YOH-reinstatement of alcohol seeking ( Aziz et al, 2016 ). Conversely, other studies have found that NOP antagonists and NOP knockout mice produce anti-obesity and anti-depressant effects (review by Witkin et al, 2014 ), and the orally bioavailable, brain-penetrant, NOP antagonist LY2940094 blocked YOH-reinstatement of alcohol seeking in alcohol-preferring rats ( Rorick-Kehn et al, 2016 ).…”