Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats

Abstract

Rationale-Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1−17) in structure and functions. Dynorphin and other kappa opioid receptor agonists have been shown to block cocaine sensitization.Objective-The present study was designed to examine the ability of OFQ/N to block cocaineinduced behavioral sensitization.Methods-Rats were habituated to testing chambers for 1 h, injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further 1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was doubled on each subsequent day. Rats were then challenged with cocaine (7.5 mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The ability of OFQ/N to block the contextindependent component of cocaine sensitization was also tested wherein rats were treated in their home cages on days 1−3. Finally, the effect of intra-VTA OFQ/N administration on cocaine sensitization was examined.Results-Sensitization did not develop in rats repeatedly treated with OFQ/N, via either route of administration, prior to cocaine administration on days 1−3. The inhibitory effect of OFQ/N was not dependent on context and was blocked by pretreatment with J-113397.Conclusion-Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization through activation of the ORL-1 receptor and that the VTA may be one of the substrates for this action of OFQ/N.

Alterations in the level of OFQ/N-IR in rat brain regions by cocaine

“…The previous study used a protocol of chronic cocaine infusion known to produce tolerance to the motor stimulatory action of cocaine (King et al 1992;Reith et al 1987). On the other hand, the present study determined the level of OFQ/N-IR under a repeated cocaine treatment paradigm that induces sensitization to the locomotor stimulatory effects of cocaine (Lutfy et al 2002), which was confirmed in the current study (Fig. 3).…”

“…For example, we have shown that intra-VTA administration of OFQ/N reduced cocaine-induced motor stimulation and also blocked locomotor sensitization induced by repeated intermittent cocaine administration (Lutfy et al 2002). The current neurochemical data demonstrating that the level of OFQ/N-IR was reduced by acute cocaine treatment raises the possibility that cocaine may cause the release of OFQ/N along the mesocorticolimbic dopaminergic pathway and might be a means through which the action of cocaine can be auto-regulated.…”

“…Previous neurochemical (Murphy and Maidment 1999;Murphy et al 2004), dual in situ hybridization (Norton et al 2002), electrophysiological (Zheng et al 2002) and behavioral (Lutfy et al 2002;Narayanan et al 2004) studies have demonstrated that VTA could be one of the brain regions where OFQ/N exerts its modulatory actions on mesolimbic dopaminergic neurons and alters the actions of cocaine and other drugs of abuse. For example, we have shown that intra-VTA administration of OFQ/N reduced cocaine-induced motor stimulation and also blocked locomotor sensitization induced by repeated intermittent cocaine administration (Lutfy et al 2002).…”

“…Thus, intracerebroventricular OFQ/N administration has been reported to attenuate elevations in accumbal dopamine induced by morphine (Di Chiara et al 1999) or cocaine (Lutfy et al 2001). Furthermore, OFQ/N has been shown to block the development of behavioral sensitization (Lutfy et al 2002), raising the possibility that the endogenous OFQ/N/ORL-1 receptor system may be involved in the phenomenon of locomotor sensitization. Thus, the present study was designed to determine whether repeated cocaine treatment that induces locomotor sensitization would alter the level of endogenous OFQ/N in various brain regions in rats.…”

The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine

“…Specifically, in situ hybridization and immunohistochemical studies have demonstrated localization of the ORL-1 receptor in the ventral tegmental area (VTA) Norton et al, 2002), where the cell bodies of the mesolimbic dopaminergic reward circuitry originate. Consistent with its localization, behavioral studies have shown that OFQ/N suppresses basal motor activity (Devine et al, 1996;Lutfy et al, 2001), at least in part, through an action in the VTA (Lutfy et al, 2002;Narayanan et al, 2004). …”