Peripheral receptors mediate the aversive conditioning effects of morphine in the rat

Abstract

Previous evidence has shown that morphine produces positive reinforcing effects (as measured in the place conditioning paradigm) through an action in the central nervous system (CNS). The aversive conditioning effects of morphine (as measured in the place and taste conditioning paradigms) were produced when drug action was restricted to peripheral sites, particularly in the gut region. We now demonstrate that most of the aversive conditioning effects of morphine (using place and taste conditioning paradigms) are receptor mediated effects exerted through an action on peripheral opiate receptors. The conditioned taste aversions induced by intraperitoneal (IP) morphine (15 mg/kg) but not amphetamine (1 mg/kg) were attenuated by low IP doses of opiate antagonists (1.0 mg/kg of naltrexone or 1 mg/kg of the peripherally acting antagonist methynaltrexone (MN)). Morphine-, but not amphetamine-induced conditioned taste aversions were also attenuated in animals whose small sensory neurons, bearing the majority of primary afferent opiate receptors, were destroyed by neonatal treatments with capsaicin. In the place conditioning paradigm, the aversive conditioning effects produced by low IP administrations of morphine were blocked by opiate antagonists. Intraperitoneal pretreatments with 1 mg/kg of the quaternary opiate antagonist MN (which does not cross the blood-brain barrier effectively) were shown to block the conditioned place aversions produced by low IP doses of morphine (0.05 mg/kg), but not the place aversions produced by lithium chloride (75 mg/kg IP), or by high doses of naloxone (10 mg/kg SC). These results demonstrate that the aversive conditioning effects of morphine are primarily mediated through an action on peripheral opiate receptors. Further results showing that MN pretreatments (1 mg/kg IP) as well as neonatal capsaicin treatments did not attenuate the positive reinforcing effect of morphine (10 mg/kg SC), as shown in the place conditioning paradigm, provide support to the notion that the neuronal systems mediating the aversive effects of opiates are independent of the systems mediating the positive reinforcing of opiates.