Roberto Ciccocioppo, Daina Economidou, Serena Stopponi, Nazzareno Cannella, Simone Braconi, Marsida Kallupi, Giordano de Gugliemo, Maurizio Massi.
Pharmacological, molecular, and genetic data generated at both the preclinical and clinical levels implicate numerous stress-related neuropetidergic systems in the regulation of aspects of alcohol abuse. Among these, substantial evidence indicates involvement of the Nociceptin/Orphain FQ N/OFQ system: several publications have demonstrated that N/OFQ regulates ethanol preference, ethanol reward, and ethanol-seeking behavior (Ciccocioppo et al., 2004; Economidou et al., 2006; Kuzmin, et al., 2007). Specifically, activation of NOP receptors by N/OFQ has been shown to inhibit home cage ethanol drinking as well as operant ethanol self-administration (Ciccocioppo et al., 2004; Economidou et al., 2006). N/OFQ also reduces both ethanol-induced conditioned place preference and conditioned reinstatement of alcohol seeking (Ciccocioppo et al., 2004). Moreover, N/OFQ inhibits stress-induced ethanol-seeking and exerts general anti-stress effects by acting as a functional antagonist of extrahypothalamic corticotropin-releasing factor (CRH) transmission (Ciccocioppo et al., 2003; Martin-Fardon et al., 2000).
Previous studies have also shown that subchronic administration of N/OFQ or N/OFQ analogues significantly reduces ethanol self-administration in genetically selected alcohol preferring Marchigian Sardinian msP rats (Ciccocioppo et al., 2004; Economidou et al., 2006). In contrast, in nonselected Wistars tested under the same experimental conditions, N/OFQ did not alter ethanol consumption (Economidou et al., 2008). In situ hybridization studies revealed higher expression levels of N/OFQ and NOP receptor mRNA in numerous brain areas of msP compared to Wistar rats. In particular, significantly higher levels of N/OFQ mRNA have been found in the bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) of msP rats; again, in these animals, the NOP receptor transcript was higher in the CeA and the basolateral amygdala (BLA). Receptor autoradiography revealed that these gene expression changes were accompanied by significant increases in NOP receptor binding within several brain areas, including the CeA, the BNST, the ventral tegmental area, and several cortical structures (Economidou et al., 2008).
These observations are indicative of an innate upregulation of the N/OFQ-NOP system in msP rats. However, while a consistent up-regulation of NOP receptor expression, binding and signaling was observed in msP rats in a majority of brain regions, a distinct and unexpected pattern of differences was found in the CeA. In this brain region, N/OFQ-stimulated [35S]GTPγS binding was significantly lower in msP than in Wistars despite elevated NOP receptor expression and binding in the msP line. This finding suggests that although the N/OFQ system is generally upregulated in msP rats, “uncoupling” of the NOP receptor from G-protein-mediated signal transduction in CeA leads to a regionally-selective dysfunction of the N/OFQ system in the CeA. Consistent with the reduction of ethanol intake by N/OFQ in msP rats, the hypofunction of the system in the CeA may facilitate alcohol drinking in this line of rats. This hypothesis is supported by data showing that stimulation of NOP receptors in the CeA by site-specific microinjection of N/OFQ reduces alcohol self-administration in msP rat (Economidou et al., 2008).
Translation of neuropeptide-mediated effects into clinical treatments has typically proven difficult. However, recent data showing that the opioid agonist/partial agonist buprenorphine reduces alcohol intake in msP rats via activation of NOP receptors (Ciccocioppo et al., 2007) not only confirm a possible link between N/OFQ and excessive alcohol consumption, but suggest a possible path toward clinical applications. Buprenorphine has long been in clinical use for the treatment of pain (Picard et al., 1997) and management of heroin dependence (Johnson et al., 2000; Kakko et al., 2003). Our findings with buprenorphine provide “proof of concept” for the feasibility of targeting central NOP receptors via peripheral drug administration to suppress excessive alcohol intake. In addition, as reported in clinical studies, in heroin addicts, buprenorphine given at doses higher than those needed to occupy opioid receptors is beneficial in controlling cocaine addiction (Montoya et al., 2004): another study showed that in heroin addicts, it not only lowers opiate consumption, but also decreases alcohol intake (Kakko et al., 2003).
These findings point toward the possibility that these effects of buprenorphine are mediated by activation of NOP receptors. Altogether, these data provide strong rationale for the development of N/OFQ receptor agonists as new therapeutics for the treatment of alcohol addiction.