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 alcohol-induced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.

Keywords: addiction; alcoholism; allostasis; dependence; drinking; hyperkatifeia; pain.

Figure 1:

Experimental Timeline.

Figure 2:

Effect of BD-1063 on ethanol (EtOH) intake (A), water intake (C), ethanol preference (D), and food intake (E). Data are normalized by body weight and represent Mean ± SEM. * p≤ 0.05, ** p≤ 0.01, *** p≤ 0.001 vs. Veh (Newman Keul’s test). (B) Correlation between the % reduction of ethanol intake by the 30 mg/kg dose of BD-1063 and the 2hr (left) and 6hr (right) ethanol intake under vehicle (Veh) conditions.

Figure 3:

Effect of BD-1063 on sucrose intake (A) and water intake (B). Data are normalized by body weight and represent Mean ± SEM.

Figure 4:

Effect of BD-1063 on thermal sensitivity (paw withdrawal threshold) (A). Data represent Mean ± SEM. * p≤ 0.05 vs. Veh; # p≤ 0.05 vs. Ctrl (Newman Keul’s test). . (B) Lack of correlation between the Paw withdrawal latency under vehicle (Veh) conditions and the 24h ethanol intake under vehicle (Veh) conditions. (C) Lack of correlation between the % reduction of decreased paw withdrawal latency by the 30 mg/kg dose of BD-1063 and the 24h ethanol intake under vehicle (Veh) conditions.

Figure 5:

Effect of BD-1063 on locomotor activity across time (A) and during the entire observation period (B). Data represent Mean ± SEM.