title: Synergy between mu/delta-opioid 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 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-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 delta 1-opioid receptor agonist, and [D-Ala2,Cys4]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-Ala2,Cys4]deltorphin when combined with the highly selective mu-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 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.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Cahill
authors.forename: T D
authors.initials: TD
authors.lastname: White
authors.forename: J
authors.initials: J
authors.lastname: Sawynok
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D004357:Drug Synergism; D004723:Endorphins / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism*
chemical_list: D004723:Endorphins; D004745:Enkephalins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C044708:morphiceptin, N-Me-Phe(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D000241:Adenosine