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Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; α) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline α values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists. SIGNIFICANCE STATEMENT Abuse of opioids has risen rapidly and continues to be a major health crisis. Thus, there is an urgent need to better understand the neurobiological and behavioral mechanisms underlying opioid addiction. Here, we investigate the role of orexin-1 receptor signaling (OxR1) within ventral pallidum (VP) in remifentanil demand and cue-induced reinstatement of remifentanil seeking. Using a within-session behavioral economics procedure, we show that intra-VP microinjections of the OxR1 antagonist SB-334867 decreased motivation (increased demand elasticity) without affecting remifentanil consumption at low effort. We also found that SB microinjected intra-VP attenuated cue-induced reinstatement of remifentanil seeking. Together, our results support a role for VP OxR1 signaling in opioid reward.

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil