Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast acting opioid remifentanil

Abstract

For submission to the special issue: 'Orexin/hypocretin receptor antagonists for the treatment of addiction and related psychiatric disease: What are the steps from here?' (Eds. Aston-Jones and James). Abstract:The orexin (hypocretin) system is important for reward-seeking behavior. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the shortacting opioid remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24h, but not on a third test at 48h. When injected locally into caudal ventral pallidum (cVP) the effects of SB were more persistent, with reduced motivation observed for up to 48h. We next made SB injections into cVP 24h prior to behavioral testing; this produced persistent effects that persisted for at least 72h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24h prior. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations might have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

“…Our laboratory and others have shown that systemic administration of the OxR1 antagonist SB attenuates drug seeking beyond the bioavailability of the compound [15,31]. Consistent with this, here we report that in rats with limited drug access, 30 mg/kg suvorexant increased fentanyl demand elasticity for ~24h.…”

“…Evidence generally supports a functional dichotomy for OxR1 vs OxR2 signaling, whereby OxR1 signaling preferentially mediates reward behaviors and OxR2 signaling modulates arousal and sleep [5]. Consistent with this, systemic treatment with selective OxR1 antagonists, including SB334867 (SB), reduce economic demand and cued reinstatement for all drugs of abuse tested, including the opioids fentanyl and remifentanil [14,15], but have limited effects on arousal and sleep [16][17][18]. In contrast, selective OxR2 antagonists promote sleep [18], and were reported to have limited effect on cocaine seeking behavior [19].…”

“…Test days were separated by at least two regular sessions, and continued until Qo and α values were stable, i.e., within ± 25% of pre-treatment values (baseline); this allowed us to test and account for potential persistent effects of suvorexant on subsequent sessions [15,31].…”

“…When administered systemically, the OxR1 antagonist SB was previously found to attenuate addiction-like behaviors beyond its bioavailability [15,31]. Here we examined whether suvorexant had similarly persistent effects on fentanyl demand.…”

The ventral pallidum and relapse in alcohol seeking

“…lesions, pharmacological, chemogenetic and optogenetic) consistently and robustly implicate the VP in a variety of forms of relapse to seeking a variety of drugs of abuse, including alcohol, cocaine, heroin, remifentanil and natural reinforcers such as sucrose and food (e.g. Mahler et al, 2014; Mohammadkhani, James, Pantazis, & Aston‐Jones, 2020; Perry & McNally, 2013; Rogers, Ghee, & See, 2008; Smith & Berridge, 2005; Tang, McFarland, Cagle, & Kalivas, 2005). Indeed, the role of the VP in different forms of relapse to seeking a variety of drugs of abuse is so robust that the VP was proposed as key component of a “final common pathway” for relapse (Kalivas & Volkow, 2005) (Figure 1a).…”