Synergy between μ/δ-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 μ-and subclasses of δ-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 μ-opioid receptors. Subnanomolar (10^-10, 10^-11 M) concentrations of the μ-opioid receptor agonists morphine, [N-MePhe³,D-Pro⁴]morphiceptin, and [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]enkephalin (DAMGO) have minimal effects on the release of adenosine from the spinal cord. However, [D-Pen²,D-Pen⁵]enkephalin (DPDPE), a δ₁-opioid receptor agonist, and [D-Ala₂,Cys₄]deltorphin, a δ₂-opioid receptor agonist, at doses which exhibit no intrinsic effects (10^-8 and 10^-7 M), shifted the dose-response curve for μ-opioid receptor-evoked adenosine release to the left in a dose-dependent manner. DPDPE was more potent than [D-Ala₂,Cys₄]deltorphin when combined with the highly selective μ-opioid receptor agonist [N-MePhe₃,D-Pro₄]morphiceptin, but these agents showed similar activity with the less selective agonists DAMGO and morphine. Simultaneous activation of μ-and δ-opioid receptors generates a synergistic release of adenosine from spinal cord synaptosomes. Although agonists for both δ₁-and δ₂-opioid receptor subtypes produce this response, the δ₁-opioid receptor agonist is more potent at eliciting this effect when the most selective μ-opioid receptor ligand is used.