Role of Mu and Delta Opioid Receptors in Alcohol Drinking Behaviour

Abstract

The dopaminergic mesolimbic system plays a key role in the mechanisms of reinforcement elicited by alcohol (ethanol) and other drugs of abuse. Numerous lines of evidence indicate that ethanol reinforcement mechanisms involve, at least partially, the ethanol-induced activation of the endogenous opioid system. Ethanol may alter opioidergic transmission at different levels, including the biosynthesis, release, and degradation of opioid peptides, as well as binding of endogenous ligands to opioid receptors. Several studies suggest that mu and delta opioid receptors play a major role in ethanol reinforcement and dependence. These studies implicate enkephalins and beta-endorphin as physiological mediators of ethanol's actions in the brain. In this review we describe the pharmacological characteristics of opioid receptors and their distribution in brain, as well as the major functions of their endogenous ligands. Thereafter, we present evidence supporting the participation of mu and delta opioid receptors in ethanol reinforcement mechanisms and high alcohol drinking behaviour. The use of opioid receptor agonists and antagonists, as well as ethanol-preferring selected rodents and knockout mice, has contributed to understand the role of mu and delta receptors in these processes. The effects of ethanol on binding of selective ligands to opioid receptors in different experimental models are also reviewed. The relevance of opioid receptors in human alcoholism is further evidenced by the association of mu receptor polymorphisms with ethanol dependence. The clinical implication of these findings is discussed regarding the differential responses observed in some alcoholic patients to treatment with opioid receptor antagonists such as naltrexone.

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…While DOR and KOR gene variants and expression have been associated with vulnerability to addiction (Margolis et al. 2008; Mendez and Morales‐Mulia 2008; Nielsen et al. 2013), some of the mechanisms involved were suggested to be acting through regulation of dopamine dynamics in vivo (Nielsen et al.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Reward and Addiction. Although immunohistochemical (Cahill et al, 2001a) and in situ hybridization studies (Mansour et al, 1994), as well as studies with DOPr-eGFP knock-in mice Scherrer et al, 2006), identify DOPr in mesolimbic brain structures important for reward and reinforcement, administration of DOPr agonists produced conflicting results in outcome measures of reward and addictive behaviors (Méndez and Morales-Mulia, 2008;Shippenberg et al, 2008;Rodríguez-Arias et al, 2010;Pradhan et al, 2011;Mitchell et al, 2014). Some studies report that DOPr agonists do not produce a place preference in otherwise drug-naïve animals (Hutcheson et al, 2001;Mitchell et al, 2014) but will after prolonged ethanol consumption (Mitchell et al, 2014).…”

Participación de los sistemas endógenos de péptidos opioides en los mecanismos de reforzamiento y dependencia al alcohol

“…Nuestros estudios iniciales se centraron en estudiar los efectos de la administración aguda de una dosis alta de etanol sobre la unión de ligandos selectivos de los recep- Los estudios descritos sugieren que las propiedades reforzadoras del etanol podrían ser parcialmente mediadas por mecanismos de regulación positiva y negativa de los receptores µ y δ en distintas áreas de las vías mesocorticolímbica y nigroestriatal (para revisiones, ver Méndez y Morales-Mulia, 2008a,b). 44,45 De acuerdo con esta propuesta, los receptores µ en el ATV desempeñarían un papel crucial en la regulación de la actividad DAérgica del sistema mesocorticolímbico en respuesta a etanol, mientras que los receptores µ y δ tendrían un papel preponderante en el NAcc y la corteza prefrontal. En la vía nigroestriatal, ambos tipos de receptores cumplirían un papel importante a nivel de la substantia nigra (SN), pero sólo los receptores δ parecen estar implicados en la modulación DAérgica en el CP.…”