Nealey KA, Smith AW, Davis SM, Smith DG, Walker BM. kappa-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats. Neuropharmacology 61: 35-42

Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Mail Code: 644820, Pullman, WA 99164-4820, USA.
Neuropharmacology (Impact Factor: 5.11). 02/2011; 61(1-2):35-42. DOI: 10.1016/j.neuropharm.2011.02.012
Source: PubMed


Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable to those that target μ- and δ-opioid receptor mechanisms alone.

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    • "Recent data show that blockade of the κ opioid system can also block the aversive stimulus effects of drug withdrawal and stress, and excessive escalated drug self-administration can also be blocked by κ antagonists (Koob 2013; Chartoff et al. 2012; Walker et al. 2011; Wee et al. 2009; Schlosburg et al. 2013). These effects may be mediated by the shell of the nucleus accumbens (Nealey et al. 2011; Schlosburg et al. 2013) and central nucleus of the amygdala (Gilpin et al. 2013; Kallupi et al. 2013). These results suggest a within-/ between-system neuroadaptation that was originally hypothesized by Carlezon and Nestler (Carlezon et al. 1998), in which activation of CREB by excessive dopamine and opioid peptide receptor activation in the nucleus accumbens trigger the induction of dynorphin to feedback to suppress dopamine release. "

    Psychopharmacology 06/2014; 231(19). DOI:10.1007/s00213-014-3623-1 · 3.88 Impact Factor
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    • "Nalmefene (m and k opioid antagonist) in the CeA Y Y 6e10 h Nealey et al. 2011 Nalmefene (m and k opioid antagonist) and CTOP þ Naltrindole (m and d antagonist) in the NAc shell "
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    • "Evidence from our laboratory has shown that k opioid receptor antagonism with a small-molecule k antagonist selectively blocked responding on a progressive-ratio schedule for cocaine in rats with extended access (Wee et al., 2009). Even more compelling is that excessive drug self-administration can also be blocked by k antagonists (Walker et al., 2010; Wee et al., 2009; Whitfield et al., 2011; Schlosburg et al., 2011) and may be mediated by the shell of the nucleus accumbens (Nealey et al., 2011). However, the neurobiological circuits involved in mediating the effects of activation of the dynorphinek opioid system on the escalation of methamphetamine intake with extended access, the specific sites of action for k receptor antagonists to mediate dramatic effects of a k antagonist on the escalation of methamphetamine selfadministration with extended access, and the signaling cascades that mediate the activation of the dynorphinek opioid system on the escalation of methamphetamine self-administration remain unknown. "
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