Regulations of opioid dependence by opioid receptor types

Three major types of opioid receptors, designated mu, delta, and kappa, are widely expressed in the CNS. Development of selective receptor ligands and recent cloning of each receptor have contributed greatly to our increasing knowledge of the neuropharmacological profile of each opioid receptor type. It is of interest to note that they include noncompetitive and allosteric interactions among their types. This review focuses on the functional interaction among these opioid receptor types that contribute to opioid dependence. Various studies provide arguments to support substantial roles for mu-opioid receptors and the possible involvement of delta-opioid receptors in the development of physical and psychological dependence on morphine. Noradrenergic transmission originating in the locus coeruleus is most likely to play the primary causal role in the expression of physical dependence on morphine. In contrast, many studies have pointed to the mesolimbic dopaminergic pathway projecting from the ventral tegmental area to the nucleus accumbens as a critical site for the initiation of psychological dependence on opioids. It is noteworthy as the broad existence of opposing interactions between mu/delta- and kappa-receptors in the brain. The activation of kappa-receptors leads to the suppression of unpleasant mu/delta-mediated side effects such as the rewarding effect. Considering the functional interaction among opioid receptor types, the co-administration of morphine-like compounds with kappa-receptor agonists may constitute a preferable and superior approach to the treatment of pain with fewer side effects.