Orexin-1 receptor signaling in ventral pallidum regulates demand for the opioid remifentanil

Signaling at the orexin-1 receptor (Ox1R) is important for motivation for various drugs of abuse. Recently, our laboratory showed that systemic blockade of Ox1Rs decreased motivation for the potent and short-acting opioid remifentanil, as well as remifentanil consumption at null cost (Porter-Stransky et al., 2017). However, the central site(s) through which orexin acts to regulate opioid-seeking behaviors are not known. We investigated ventral pallidum (VP) as a potential site of orexin action, as VP is a known mediator of opioid reward and is densely innervated by orexin-immunoreactive fibers. We used a within-session behavioral economics (BE) paradigm in which remifentanil price (responses/ μg iv remifentanil) was sequentially increased throughout the session. Rats were implanted with bilateral cannulae into caudal VP (cVP), through which microinjections of SB334867 (SB), an Ox1R antagonist, were given prior to BE and reinstatement testing. Contrary to systemic SB treatment, intra-cVP SB preferentially reduced motivation (increased demand elasticity and reinstatement) for reminfentanil, without affecting remifentanil consumption at null cost. These effects were specific to cVP, as control microinjections of SB immediately dorsal to cVP did not affect remifentanil-seeking. Baseline demand for remifentanil predicted cued reinstatement of remifentanil seeking and the efficacy with which intra-cVP SB administration reduced motivation for remifentanil. These findings indicate a specific role for cVP Ox1R signaling in mediating the motivational properties of the opioid remifentanil, distinct from its consumption at null cost. Our findings also highlight the BE paradigm as an effective biomarker for predicting opioid addiction behaviors and treatment efficacy.