Antagonism of Sigma-1 Receptor Blocks Heavy Alcohol Drinking and Associated Hyperalgesia in Male Mice

Overview

Journal Alcohol Clin Exp Res

Specialty Psychiatry

Date 2021 Jun 1

PMID 34060104

Citations 5

Authors

Sema G Quadir

Sean M Tanino

Yasmine N Sami

Margaret A Minnig

Malliga R Iyer

Kenner C Rice

Pietro Cottone

Valentina Sabino

Affiliations

Soon will be listed here.

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.

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References

Choi S, Roh D, Yoon S, Kang S, Moon J, Kwon S . Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats. Pharmacol Res. 2013; 74:56-67. DOI: 10.1016/j.phrs.2013.05.004. View

Quadir S, Tanino S, Rohl C, Sahn J, Yao E, Cruz L . The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice. Neuropharmacology. 2020; 184:108409. PMC: 7856185. DOI: 10.1016/j.neuropharm.2020.108409. View

Sabino V, Cottone P, Zhao Y, Steardo L, Koob G, Zorrilla E . Selective reduction of alcohol drinking in Sardinian alcohol-preferring rats by a sigma-1 receptor antagonist. Psychopharmacology (Berl). 2009; 205(2):327-35. PMC: 2748837. DOI: 10.1007/s00213-009-1548-x. View

Moore C, Leonard M, Micovic N, Miczek K, Sabino V, Cottone P . Reward sensitivity deficits in a rat model of compulsive eating behavior. Neuropsychopharmacology. 2019; 45(4):589-596. PMC: 7021808. DOI: 10.1038/s41386-019-0550-1. View

Quadir S, Rohl C, Zeabi A, Moore C, Cottone P, Sabino V . Effect of different standard rodent diets on ethanol intake and associated allodynia in male mice. Alcohol. 2020; 87:17-23. PMC: 7812484. DOI: 10.1016/j.alcohol.2020.04.003. View

Gianoulakis C . Influence of the endogenous opioid system on high alcohol consumption and genetic predisposition to alcoholism. J Psychiatry Neurosci. 2001; 26(4):304-18. PMC: 167184. View

Carcole M, Zamanillo D, Merlos M, Fernandez-Pastor B, Cabanero D, Maldonado R . Blockade of the Sigma-1 Receptor Relieves Cognitive and Emotional Impairments Associated to Chronic Osteoarthritis Pain. Front Pharmacol. 2019; 10:468. PMC: 6510262. DOI: 10.3389/fphar.2019.00468. View

Bura A, Guegan T, Zamanillo D, Vela J, Maldonado R . Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain. Eur J Pain. 2012; 17(6):832-43. DOI: 10.1002/j.1532-2149.2012.00251.x. View

Kinoshita M, Matsuoka Y, Suzuki T, Mirrielees J, Yang J . Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands. Brain Res. 2012; 1452:1-9. PMC: 3670091. DOI: 10.1016/j.brainres.2012.02.070. View

10.

Martin W, EADES C, Thompson J, Huppler R, Gilbert P . The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976; 197(3):517-32. View

11.

George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen C . Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking. Proc Natl Acad Sci U S A. 2012; 109(44):18156-61. PMC: 3497825. DOI: 10.1073/pnas.1116523109. View

12.

Quadir S, Cottone P, Sabino V . Role of Sigma Receptors in Alcohol Addiction. Front Pharmacol. 2019; 10:687. PMC: 6586921. DOI: 10.3389/fphar.2019.00687. View

13.

Valenza M, Blasio A, DiLeo A, Cottone P, Sabino V . Sigma receptor-induced heavy drinking in rats: Modulation by the opioid receptor system. Pharmacol Biochem Behav. 2020; 192:172914. PMC: 9551643. DOI: 10.1016/j.pbb.2020.172914. View

14.

Brammer M, Gilmore D, Matsumoto R . Interactions between 3,4-methylenedioxymethamphetamine and sigma1 receptors. Eur J Pharmacol. 2006; 553(1-3):141-5. PMC: 1780037. DOI: 10.1016/j.ejphar.2006.09.038. View

15.

Wise R . Voluntary ethanol intake in rats following exposure to ethanol on various schedules. Psychopharmacologia. 1973; 29(3):203-10. DOI: 10.1007/BF00414034. View

16.

Dore R, Iemolo A, Smith K, Wang X, Cottone P, Sabino V . CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP. Neuropsychopharmacology. 2013; 38(11):2160-9. PMC: 3773665. DOI: 10.1038/npp.2013.113. View

17.

Gris G, Merlos M, Vela J, Zamanillo D, Portillo-Salido E . S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice. Behav Pharmacol. 2014; 25(3):226-35. DOI: 10.1097/FBP.0000000000000038. View

18.

Hayashi T, Su T . Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells. J Pharmacol Exp Ther. 2003; 306(2):726-33. DOI: 10.1124/jpet.103.051292. View

19.

Fu R, Gregor D, Peng Z, Li J, Bekker A, Ye J . Chronic intermittent voluntary alcohol drinking induces hyperalgesia in Sprague-Dawley rats. Int J Physiol Pathophysiol Pharmacol. 2016; 7(3):136-44. PMC: 4697669. View

20.

Sabino V, Cottone P, Blasio A, Iyer M, Steardo L, Rice K . Activation of σ-receptors induces binge-like drinking in Sardinian alcohol-preferring rats. Neuropsychopharmacology. 2011; 36(6):1207-18. PMC: 3079320. DOI: 10.1038/npp.2011.5. View