Antagonism of Sigma‐1 receptor blocks heavy alcohol drinking and associated hyperalgesia in male mice

Abstract

Background: Alcohol use disorder (AUD) is a complex psychiatric disease characterized by high alcohol intake as well as hyperkatifeia and hyperalgesia during withdrawal. A role for Sigma-1 receptors (Sig-1Rs) in the rewarding and reinforcing effects of alcohol has started to emerge in recent years, as rat studies have indicated that Sig-1R hyperactivity may result in excessive alcohol drinking. Sig-1R studies in mice are very scarce, and its potential role in alcohol-induced hyperalgesia is also unknown. Methods:In this study, we investigated the role of Sig-1R in alcohol drinking and associated hyperalgesia in male mice, using an intermittent access 2-bottle choice model of heavy drinking. Results:The Sig-1R antagonist BD-1063 was found dose dependently to reduce both alcohol intake and preference, without affecting either water or sucrose intake, suggesting that the effects are specific for alcohol. Notably, the ability of BD-1063 to suppress ethanol intake correlated with the individual baseline levels of alcohol drinking, suggesting that the treatment was more efficacious in heavy drinking animals.In addition, BD-1063 reversed alcohol-induced hyperalgesia during withdrawal, assessed using an automatic Hargreaves test, without affecting thermal sensitivity in alcohol-naïve animals or locomotor activity in either group.Conclusions: These data show that Sig-1R antagonism dose-dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcoholinduced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.

2-Arachodonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice

“…The findings are not easily compared between studies using different routes of administration and time of testing in withdrawal. Overall, the data presented here agree with literature showing three days as the optimal withdrawal time for induction hyperalgesia in mice following chronic alcohol drinking in a twobottle choice model [128,129]. Under the current experimental conditions of 72-hour withdrawal from alcohol, the effects on mechanical sensitivity and anxiety-like behaviors appear dissociable.…”

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats

“…Notably, there were no group effects of EtOH drinking on pain sensitivity or affective behavior. While previous studies have seen effects of EtOH on pain sensitivity and affect (Quadir et al, 2021b) (Gong et al, 2017;Overstreet et al, 2005;Van Skike et al, 2015;Xu et al, 2021), others studies have not (Bloch et al, 2020;McNamara and Ito, 2021;Pirino et al, 2022) One potential explanation is that rats in the present study only drank for 3-4 weeks before behavioral testing and thus did not consume enough EtOH to produce behavioral deficits. Studies in Wistar rats report escalated intake after ~20 EtOH drinking sessions (Carnicella et al, 2009;George et al, 2012;Kimbrough et al, 2017); rats in this study only drank for 16 sessions.…”

“…These findings are in accordance with a previous study reporting that EtOH withdrawal increases nociceptive threshold(Schunck et al, 2015). However, it is important to note that many other studies have demonstrated EtOH-induced decreases in pain threshold (Avegno et al, 2018; Kang et al, 2019; Kononoff et al, 2018; Quadir et al, 2020a; Quadir et al, 2021a; Quadir et al, 2021b; Walcott et al, 2018; You et al, 2020). Our findings suggest male CRF1:cre: td Tomato rats may be resistant to the analgesic properties of EtOH; however, further studies will test thermal sensitivity during intoxication to directly address this speculation.…”

“…Intermittent access two bottle choice alcohol drinking was performed as previously described (Quadir et al, 2022; Quadir et al, 2020b; Quadir et al, 2021b; Wise, 1973). After 4d acclimatization to water bottle drinking, one bottle containing 20% EtOH and one bottle of water for 24h were placed on cages on alternating days.…”

“…Many studies have reported increased negative affect following chronic EtOH drinkingt 36,[79][80][81][82] . However, there were no group effects of EtOH on thermal sensitivity or anxiety-and depressive-like behavior in the studies presented here.…”