Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies

Abstract

The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins). The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the specific contribution of each component of these endogenous systems in vivo on reward process. This review will summarize available genetic tools and our present knowledge on the consequences of gene knockout on reinforced behaviors in both systems, with a focus on their potential interactions. A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals.

Keywords: G protein-coupled receptors; cannabinoid; genetically modified mice; opioid; reward.

FIGURE 1

Schematic representation of the distribution of mu opioid and CB1 cannabinoid receptors in the central nervous system. CB1 receptor distribution over the whole central nervous system is indicated by circle shapes with low (white), moderate (gray) and high (dark gray) expression. Major localization of CB1 receptor (mRNA and protein) is in cortical areas, amygdala, striatum, and cerebellum. Moderate and low expression levels are observed in thalamic, hypothalamic, and brainstem regions. Interestingly, the mu opioid receptor is also expressed in these CB1 expressing brain areas but at various levels, indicated by diamonds for low (one), moderate (two), and high (three) expression levels (adapted from Mackie, 2005; Erbs et al., 2014 and references therein). Amb, ambiguous nucleus; BLA, basolateral amygdala; CeA, central amygdala; CPu, caudate putamen; DB, diagonal band; DRN, dorsal raphe nucleus; GP, globus pallidus; Hyp, hypothalamus; LC, locus coeruleus; LHb, lateral habenular nucleus; mHb, medial habenular nucleus; NAc, nucleus accumbens; OB, olfactory bulb; PAG, periaqueductal gray; SNr, substantia nigra pars reticulate; Sol, nucleus of the solitary tract; STh, subthalamic nucleus (ventral thalamus); Th, dorsal thalamus; Tu, olfactory tubercle; VTA, ventral tegmental area.