Opposite motivational effects of endogenous opioids in brain and periphery

Many psychoactive drugs, including the opiates, have been shown to have paradoxical reinforcing effects. Opiates produce positive reinforcing effects when they are paired with visual and textural environmental stimuli in rats, yet, at similar doses and over the same routes of administration, produce aversive effects, as shown when they are paired with taste stimuli. Similarly, in human, the positive reinforcing effects of opiates are well known to addicts and recreational drug users, yet patients receiving opiates as analgesics often report nauseous reactions. At present there is no evidence to differentiate between the neural substrates that mediate these opposite motivational effects. We now report an initial step in the resolution of this paradox by demonstrating that endogenous and exogenous opioids produce positive reinforcing effects through an action on brain opiate receptors, and aversive effects through an action on peripheral opiate receptors (especially in the gut).