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Original Article

Emergence of Functional -Opioid Receptors Induced by Long-Term Treatment with Morphine

Department of Anesthesiology and Pain Medicine, the University of Texas-MD Anderson Cancer Center, Houston, Texas (J.M., Y.Z., Z.Z.P.); and Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota (A.E.K.)

Abstract

Opioid analgesics remain the choice for the treatment of moderate to severe pain. Recent research has established that the µ-opioid receptor is predominantly responsible for mediating many opioid actions, including analgesia and opioid tolerance. However, the function of -opioid receptors is rather puzzling at present, with inconsistent reports of system effects by agonists of -opioid receptors. The functional interaction between µ-opioid receptors and -opioid receptors is also poorly understood. In this study, we demonstrated that in a brainstem site critically involved in opioid analgesia, agonists of -opioid receptors, ineffective in opioid naive rats, significantly inhibit presynaptic GABA release in the brainstem neurons from morphine-tolerant rats. In membrane preparation from control brainstem tissues, Western blot detected no proteins of -opioid receptors, but consistent -opioid receptor proteins were expressed in membrane preparation from morphine-tolerant rats. Immunohistochemical studies revealed that long-term morphine treatment significantly increases the number of -opioid receptor-immunoreactive varicosities that appose the postsynaptic membrane of these neurons. The colocalization of -opioid receptor-immunoreactive varicosities with the labeling of the GABA-synthesizing enzyme glutamic acid decarboxylase is also significantly increased. From a behavioral perspective, activation of -opioid receptors in the brainstem nucleus, lacking an effect in opioid naive rats, became analgesic in morphine-tolerant rats and significantly reduced morphine tolerance. These findings indicate that long-term morphine treatment induces the emergence of functional -opioid receptors and -opioid receptor-mediated analgesia, probably through receptor translocation to surface membrane in GABAergic terminals. They also suggest that opioid drugs with preference for -opioid receptors may have better therapeutic effect in a µ-opioid-tolerant state.

Address correspondence to: Dr. Zhizhong Z. Pan, Department of Anesthesiology and Pain Medicine, Unit 110, University of Texas-MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: zzpan{at}mdanderson.org

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