PT  - JOURNAL ARTICLE
AU  - Ma, Junyi
AU  - Zhang, Yong
AU  - Kalyuzhny, Alex E.
AU  - Pan, Zhizhong Z.
TI  - Emergence of Functional δ-Opioid Receptors Induced by Long-Term Treatment with Morphine
AID  - 10.1124/mol.105.019109
DP  - 2006 Apr 01
TA  - Molecular Pharmacology
PG  - 1137--1145
VI  - 69
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/69/4/1137.short
4100  - http://molpharm.aspetjournals.org/content/69/4/1137.full
SO  - Mol Pharmacol2006 Apr 01; 69
AB  - 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 δ-opioid receptors is rather puzzling at present, with inconsistent reports of system effects by agonists of δ-opioid receptors. The functional interaction between μ-opioid receptors and δ-opioid receptors is also poorly understood. In this study, we demonstrated that in a brainstem site critically involved in opioid analgesia, agonists of δ-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 δ-opioid receptors, but consistent δ-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 δ-opioid receptor-immunoreactive varicosities that appose the postsynaptic membrane of these neurons. The colocalization of δ-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 δ-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 δ-opioid receptors and δ-opioid receptor-mediated analgesia, probably through receptor translocation to surface membrane in GABAergic terminals. They also suggest that opioid drugs with preference for δ-opioid receptors may have better therapeutic effect in a μ-opioid-tolerant state.