Synergy between [formula omitted] receptors mediates adenosine release from spinal cord synaptosomes

Abstract

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-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 δ 1-opioid receptor agonist, and [ d-Ala 2,Cys 4]deltorphin, a δ 2-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-Ala 2,Cys 4]deltorphin when combined with the highly selective μ-opioid receptor agonist [ N-MePhe 3, d-Pro 4]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 δ 1- and δ 2-opioid receptor subtypes produce this response, the δ 1-opioid receptor agonist is more potent at eliciting this effect when the most selective μ-opioid receptor ligand is used.