MORPHINE ACTIVATES OMEGA-CONOTOXIN-SENSITIVE CA-2+ CHANNELS TO RELEASE ADENOSINE FROM SPINAL-CORD SYNAPTOSOMES

Morphine-induced release of adenosine from the spinal cord is believed to contribute to spinal antinociception. Although this release is Ca2+ dependent, little is known of the nature of this dependence. In this study, the effects of the dihydropyridine L-type Ca2+ channel agonist Bay K 8644 and the antagonist nifedipine, the N-type Ca2+ channel antagonist omega-conotoxin, and ruthenium red, a blocker of Ca2+ influx induced by capsaicin, on release of adenosine evoked by morphine were determined. The effect of partial depolarization with a minimally effective concentration of K+ on morphine-evoked release of adenosine also was examined. Morphine 10(-5)-10(-4) M produced a dose-dependent enhancement of adenosine release from dorsal spinal cord synaptosomes. Following the addition of 6 mM K+ (total K+ concentration of 10.7 mM), 10(-6) M morphine also enhanced release, and an additional component of action at 10(-8) M was revealed. Release was Ca2+-dependent as it was not observed in the absence of Ca2+ and presence of EGTA. Bay K 8644 (10 nM) and nifedipine (100 nM) had no effect on the release of adenosine evoked by morphine, but omega-conotoxin (100 nM) markedly reduced such release in both the absence and the presence of the additional 6 mM K+. Morphine-evoked adenosine release was not altered in the presence of a partially effective dose of capsaicin, nor by ruthenium red. These results indicate that morphine can stimulate two distinct phases of adenosine release from the spinal cord (nanomolar and micromolar), and that both phases of release are due to Ca2+ entry via omega-conotoxin-sensitive N-type Ca2+ channels.