PharmacologyBiochemistry & Behavior, Vol. 28, pp. 21%225. e PergamonJournals Ltd., 1987.Printedin the U.S.A. 0091-3057/87$3.00 + .00 Peripheral Receptors Mediate the Aversive Conditioning Effects of Morphine in the Rat ANTOINE BECHARA,1 KATHY A. ZITO AND DEREK VAN DER KOOY Neurobiology Research Group, Department of Anatomy, Faculty of Medicine University of Toronto, Toronto, Ontario, Canada M5S IA8 Received 21 November 1985 BECHARA, A., K. A. ZITO AND D. VAN DER KOOY. Peripheralreceptors mediate the aversive conditioning effects of morphine in the rat. PHARMACOL BIOCHEM BEHAV 28(2) 21%225, 1987.--Previous evidence has shown that mor- phine 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 condition- ing 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 (0.1 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 effects 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 effects of opiates. Morphine Methylnaltrexone Naltrexone Capsaicin Opiate aversions Place conditioning Conditioned taste aversion THE positive reinforcing as well as the aversive properties of opiates have been demonstrated in the rat. Rats prefer an environment that has been previously paired with morphine [2, 13, 28]. In contrast, experimental animals avoid novel tastes that have been paired previously with morphine given at similar doses and over the same routes of administration [5,25]. Furthermore, under certain experimental conditions animals were shown to avoid a place that had been paired previously with low intraperitoneal doses of morphine [2]. Recent evidence suggests that separate neural substrates mediate these opposite motivational effects of morphine in the rat [2]. The positive reinforcing effects of morphine are produced through an action in the brain, and the aversive conditioning effects are mediated through drug action in the periphery, especially in the gut region [2]. Although evidence exists for an anatomical specificity of morphine positive rein- forcing and aversive effects [2], the pharmacological speci- ficity of these motivational effects to the opiate receptor has not been fully clarified. Several lines of evidence showed that the positive reinforcing effects of opiates are receptor mediated [13, 21, 27]. However, questions have been raised concerning the non-specificity of opiate aversive condition- ing effects [12], although there are reports that opiate antagonists attenuate the aversive effects of morphine in the conditioned taste aversion paradigm [10,25]. The demon- stration that the aversive conditioning effects of morphine are produced through drug action in the periphery [2] now allows more exacting tests of receptor specificity through manipulations of peripheral opiate receptors. Therefore, the present experiments focus on the pharmacological specific- ity of morphine aversive conditioning effects to peripheral opiate receptors. The aversive conditioning effects of mor- phine were studied after the blockade of peripheral opiate receptors with opiate antagonists or after the destruction of 1Requests for reprints should be addressed to A. Bechara, Department of Anatomy, University of Toronto, Toronto, Ontario, Canada M5S, 1A8. 219