SPINAL OPIOID RECEPTORS AND ADENOSINE RELEASE - NEUROCHEMICAL AND BEHAVIORAL CHARACTERIZATION OF OPIOID SUBTYPES

Release of adenosine from the spinal cord contributes to spinal antino ciception by morphine. Morphine induces a Ca++-dependent release of ad enosine from dorsal spinal cord synaptosomes, which is augmented under partially depolarizing conditions. The present study examined the opi oid receptor subtypes involved in this release, and determined whether adenosine is an important mediator of antinociception induced by the spinal administration of selective opioid agonists in rats. Nanomolar and micromolar concentrations of the selective mlr opioid agonists DAM GO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin and PLO17 {[N-MePhe(3), D-Pro(4)]morphiceptin) induced release of adenosine in a biphasic mann er in the presence of a partial depolarization (addition of 6 mM K+ to the Krebs' medium). The delta opioid agonists DPDPE {[D-Pen(2),D-Pen( 5)] enkephalin) and DELT {[D-Ala(2),Cys(4)]deltorphin} and the kappa o pioid agonist U50488H 4-dichloro-N-methyl-N-(2-(1-pyrroli-zemeacetamid e) had little effect on the release of adenosine except at high microm olar concentrations. Release of adenosine by mu (nanomolar) and delta (micromolar) ligands is Ca++-dependent, whereas the kappa (micromolar) receptor ligand releases adenosine via a Ca++-independent mechanism. Behavioral antinociception using the hot-plate threshold test revealed that intrathecal administration of the my and delta opioid receptor a gonists produced dose-dependent antinociception with an order of poten cy of DAMGO, PLO17 > morphine, DELT > DPDPE. An ED(75) dose of morphin e, DAMGO or PLO17 was attenuated dose-dependently by intrathecal pretr eatment with the adenosine receptor antagonist caffeine. Caffeine did not block the antinociceptive response to delta agonists, but in fact augmented antinociception when combined with DPDPE and DELT. This augm entation was dose-dependent. This study demonstrates that activation o f the mu receptor subtype is responsible for the opioid-induced releas e of adenosine from the spinal cord, that such release contributes to the spinal antinociception by mu agonists and that only release evoked by low doses of opioids is behaviorally relevant.