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 interac tions between mu- and subclasses of delta-opioid receptors in the rele ase of adenosine. Nanomolar(10(-8), 10(-9) M) concentrations of morphi ne release adenosine from spinal cord synaptosomes under conditions of partial depolarization with elevated K+, and this component of releas e is mediated by activation of mu-opioid receptors. Subnanomolar (10(- 10), 10(-11) M) concentrations of the mu-opioid receptor agonists morp hine, [N-MePhe(3),D-Pro(4)]morphiceptin, and [D-Ala(2), N-Me-Phe(4),Gl y(5)-ol]enkephalin (DAMGO) have minimal effects on the release of aden osine from the spinal cord. However, [D-Pen(2),D-Pen(5)]enkephalin (DP DPE), a delta(1)-opioid receptor agonist, and [D-Ala(2),Cys(4)]deltorp hin, a delta(2)-opioid receptor agonist, at doses which exhibit no int rinsic 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)]deltorph in when combined with the highly selective mu-opioid receptor agonist [N-MePhe(3),n-Pro(4)]morphiceptin, but these agents showed similar act ivity with tile less selective agonists DAMGO and morphine. Simultaneo us activation of mu- and delta-opioid receptors generates a synergisti c release of adenosine from spinal cord synaptosomes. Although agonist s for both delta(1)- and delta(2)-opioid receptor subtypes produce thi s response, the delta(1)-opioid receptor agonist is more potent at eli citing this effect when the most selective mu-opioid receptor ligand i s used.