Synergy between mu/delta-opioid receptors mediates adenosine release from spinal cord synaptosomes

Morphine releases adenosine from the spinal cord and this contributes to spinal antinociception. The present study examined possible interactions between mu- and subclasses of delta-opioid receptors in the release of adenosine. Nanomolar(10(-8), 10(-9) M) concentrations of morphine release adenosine from spinal cord synaptosomes under conditions of partial depolarization with elevated K+, and this component of release is mediated by activation of mu-opioid receptors. Subnanomolar (10(-10), 10(-11) M) concentrations of the mu-opioid receptor agonists morphine, [N-MePhe(3),D-Pro(4)]morphiceptin, and [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO) have minimal effects on the release of adenosine from the spinal cord. However, [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), a delta(1)-opioid receptor agonist, and [D-Ala(2),Cys(4)]deltorphin, a delta(2)-opioid receptor agonist, at doses which exhibit no intrinsic effects (10(-8) and 10(-7) M), shifted the dose-response curve for mu-opioid receptor-evoked adenosine release to the left in a dose-dependent manner. DPDPE was more potent than [D-Ala(2),Cys(4)]deltorphin when combined with the highly selective mu-opioid receptor agonist [N-MePhe(3),n-Pro(4)]morphiceptin, but these agents showed similar activity with the less selective agonists DAMGO and morphine. Simultaneous activation of mu- and delta-opioid receptors generates a synergistic release of adenosine from spinal cord synaptosomes. Although agonists for both delta(1)- and delta(2)-opioid receptor subtypes produce this response, the delta(1)-opioid receptor agonist is more potent at eliciting this effect when the most selective mu-opioid receptor ligand is used.