The endogenous opioid system consists of mu, delta and kappa receptors. The opioidergic system may play a role in negative affect regulation via substance use [116] and there is considerable evidence that the cannabinoid and opioid systems may interact [117,118]. The mu-receptors commonly co-localize with CB1 receptors in the central nervous system [119,99,120]. Both opioids and cannabinoids produce antinociception and analgesia and animal studies have revealed considerable cross-tolerance and precipitation of cross-drug withdrawal between these two endogenous systems [121-123]. Furthermore, both cannabinoids and opioids target glutamatergic and GABAergic systems – for instance, Caille & Parsons [124] showed that a cannabinoid agonist-induced reduction in GABA could be reversed by naloxone, a competitive mu-opioid receptor antagonist. There is also mounting evidence that the motivational, cognitive and emotional responses associated with cannabinoids are cross-modulated (i.e. changes in activity of the receptor, such as CB1 when another substance, such as an opioid, binds to it) by opioids [125-128,117].
