The Journal of Neurophysiology Vol. 78 No. 2 August 1997, pp. 759-766
Copyright ©1997 The American Physiological Society

Involvement of cAMP-Dependent Protein Kinase in µ-Opioid Modulation of NMDA-Mediated Synaptic Currents

Cui-Wei Xie¹ and Darrell V. Lewis²

¹ Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, California 90024; and ² Department of Pediatrics, Division of Neurology, Duke University Medical Center, Durham, North Carolina 27713

Xie, Cui-Wei and Darrell V. Lewis. Involvement of cAMP-dependent protein kinase in µ-opioid modulation of NMDA-mediated synaptic currents. J. Neurophysiol. 78: 759-766, 1997. We have previously reported dual effects of µ-opioids on N-methyl-D-aspartate (NMDA)-receptor-mediated synaptic events in the hippocampal dentate gyrus: an indirect facilitating effect via suppression of GABAergic interneurons (disinhibition) and a direct inhibitory effect in the presence of -aminobutyric acid-A (GABA_A) antagonists. The cellular mechanism underlying the inhibitory effect of µ-opioids remains to be determined. In the present study we examine the role of adenosine 3,5-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) in µ-opioid-induced inhibition of NMDA currents in rat hippocampal slices. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) were evoked by stimulating the lateral perforant path and were recorded from dentate granule cells with the use of whole cell voltage-clamp techniques in the presence of the GABA_A antagonist and a non-NMDA type of glutamate receptor antagonist. Two selective µ-agonists, [N-MePhe³, D-Pro⁴]-morphiceptin and [D-Ala², N-MePhe⁴, Gly-ol⁵]-enkephalin, induced dose-dependent inhibition of NMDA EPSCs in a concentration range of 0.3-10 µM. This inhibitory effect could be completely reversed by the opioid antagonists naloxone or prevented by a selective µ-antagonist cyprodime, but was not affected by removal of Mg²⁺ from the external perfusion medium. Intracellular application of pertussis toxin (PTX) into the granule cell via whole cell recording pipettes completely prevented µ-opioid-induced reduction in NMDA currents, suggesting that a postsynaptic mechanism involving PTX-sensitive G proteins might be responsible for the inhibitory action of µ-opioids. Further studies were conducted to identify the intracellular messengers that coupled with G proteins and transduced the effect of µ-opioids in granule cells. The adenylate cyclase activator forskolin was found to enhance NMDA-receptor-mediated synaptic responses and to reverse the inhibitory effect of µ-opioids. Sp-cAMPS, a specific PKA activator, also enhanced NMDA EPSCs, whereas the PKA inhibitor Rp-cAMPS reduced NMDA EPSCs and occluded further inhibition of the current by µ-opioids. These findings strongly suggest that NMDA receptor function is subject to the modulation by PKA, and that µ-opioids can inhibit NMDA currents through suppression of the cAMP cascade in the postsynaptic neuron. Combined with our previous findings, the present results also indicate that µ-opioids can modulate NMDA-receptor-mediated synaptic activity in a complex manner. The net effect of µ-opioids in the dentate gyrus may depend on the interplay between its disinhibitory action, which facilitates NMDA-receptor-mediated responses, and its inhibitory action on the cAMP cascade.

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