Opioid reward mechanisms: a key role in drug abuse?

Abstract

There is increasing evidence to implicate the mesolimbic dopamine system in the rewarding effects of drugs of abuse such as opioids, psychostimulants, and alcohol, and in addition endogenous opioids may play a key role in the underlying adaptive mechanisms. Opioid agonists with affinity for mu and delta opioid receptors are rewarding, whereas opioid agonists with affinity for kappa receptors are aversive. These opposing motivational effects are paralleled by an increase and decrease, respectively, of dopamine release in the nucleus accumbens. Opposite effects are induced in response to selective antagonists for these different receptor types, pointing to tonically active endogenous opioid reward mechanisms. Withdrawal from chronic morphine results in sensitization for opioid reward; an effect that is counteracted by kappa opioid agonists. The rewarding effects of psychostimulants such as cocaine and amphetamine, mediated by the mesolimbic dopamine pathway, are modulated by opioid mechanisms in both directions: sensitization by morphine pretreatment, inhibition by kappa receptor agonists. A modulatory role of endogenous opioids is also suggested from biochemical data, showing increased dynorphin and kappa receptor expression after chronic cocaine treatment. Alcohol reward involves the mesolimbic reward system also, and opioids modulate this behaviour. Naltrexone as well as selective mu and delta opioid receptor antagonists decrease alcohol consumption in operant conditioning models. Biochemical approaches point to a functional deficit of endogenous opioids in genetic models exhibiting high prevalence for alcohol intake. The therapeutic implications of these data are discussed.