The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice

Abstract

Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol intake, loss of control over alcohol intake, and a negative emotional state when access to alcohol is prevented. AUD is also closely tied to pain, as repeated alcohol drinking leads to increased pain sensitivity during withdrawal. The sigma-2 receptor, recently identified as transmembrane protein 97 (σ2R/TMEM97), is an integral membrane protein involved in cholesterol homeostasis and lipid metabolism. Selective σ2R/Tmem97 modulators have been recently shown to relieve mechanical hypersensitivity in animal models of neuropathic pain as well as to attenuate alcohol withdrawal signs in C. elegans and to reduce alcohol drinking in rats, suggesting a potential key role for this protein in alcohol-related behaviors. In this study, we tested the effects of a potent and selective σ2R/TMEM97 ligand, JVW-1034, on heavy alcohol drinking and alcohol-induced heightened pain states in mice using an intermittent access model. Administration of JVW-1034 decreased both ethanol intake and preference for ethanol, without affecting water intake, total fluid intake, or food intake. Notably, this effect was specific for alcohol, as JVW-1034 had no effect on sucrose intake. Furthermore, JVW-1034 reduced both thermal hyperalgesia and mechanical hypersensitivity in ethanol withdrawn mice. Our data provide important evidence that modulation of σ2R/TMEM97 with small molecules can mediate heavy alcohol drinking as well as chronic alcohol-induced heightened pain sensitivity, thereby identifying a promising novel pharmacological target for AUD and associated pain states.

Keywords: Addiction; Alcoholism; Dependence; Drinking; Ethanol; Hyperalgesia; Pain; Sigma-2 receptor; Transmembrane protein 97.

Figure 1:

Experimental timeline for each cohort of animals. Cohort 1 N=18 and 2 (N=23) (shown in (A) and (B), respectively) were used for the alcohol studies, while Cohort 3 (N=7) (shown in (C)) was used for the sucrose study.

Figure 2:

JVW-1034 (A) and its effects on (B) ethanol (EtOH) intake, (C) water intake, (D) ethanol preference, and (E) food intake. N=9. Data represent Mean ± SEM. * p< 0.05, ** p< 0.01 vs. Veh (Newman Keul’s test).

Figure 3:

Effect of JVW-1034 on (A) sucrose intake and (B) water intake. N=7. Data represent Mean ± SEM. * p< 0.05, ** p< 0.01 vs. Veh (Newman Keul’s test).

Figure 4:

Effect of JVW-1034 on (A) mechanical sensitivity and (B) thermal sensitivity. N=6/group. Data represent Mean ± SEM. ** p< 0.01, *** p< 0.001 vs. Veh; ### p< 0.001 vs. Ctrl (Newman Keul’s test).

Figure 5:

Effect of JVW-1034 on locomotor activity (A) across time and (B) total. N=9 per group. Data represent Mean ± SEM.