Emergence of Functional {delta}-Opioid Receptors
Induced by Chronic Morphine

Ma J, Zhang Y, Kalyuzhny AE, Pan ZZ.
University of Texas-MD Anderson Cancer Center.
Mol Pharmacol. 2006 Jan 6;


Opioid analgesics remain the choice for the treatment of moderate to severe pain. Recent research has established that the mu-opioid receptor is predominantly responsible for mediating many opioid actions, including analgesia and opioid tolerance. However, the function of delta-opioid receptors is rather puzzling at present with inconsistent reports of system effects by agonists of delta-opioid receptors. The functional interaction between mu-opioid receptors and delta-opioid receptors is also poorly understood. In this study, we demonstrate that in a brainstem site critically involved in opioid analgesia, agonists of delta-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 delta-opioid receptors, but consistent delta-opioid receptor proteins were expressed in membrane preparation from morphine-tolerant rats. Immunohistochemical studies reveal that chronic morphine significantly increases the number of delta-opioid receptor-immunoreactive varicosities that appose the postsynaptic membrane of these neurons. The co-localization of delta-opioid receptor-immunoreactive varicosities with the labeling of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) is also significantly increased. Behaviorally, activation of delta-opioid receptors in the brainstem nucleus, lacking an effect in opioid naive rats, becomes analgesic in morphine-tolerant rats and significantly reduces morphine tolerance. These findings indicate that chronic morphine induces the emergence of functional delta-opioid receptors and delta-opioid receptor-mediated analgesia likely through receptor translocation to surface membrane in GABAergic terminals. They also suggest that opioid drugs with preference for delta-opioid receptors may have better therapeutic effect in a mu-opioid-tolerant state.
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