| dc.description | Release of adenosine from the spinal cord contributes to spinal opioid-induced antinociception. The present study examined: (1) whether morphine-evoked release of adenosine is enhanced by agents which depolarize primary afferent nerve terminals, (2) the opioid receptor subtypes and possible interactions between $\mu$ and subclasses of $\delta$ opioid receptors involved in the release of adenosine from dorsal spinal cord synaptosomes, (3) the methylxanthine-sensitivity of selective opioid receptor agonists to determine which adenosine receptor subtype induces spinal antinociception in rats. Substance P evoked the release of adenosine in a biphasic manner; this was Ca$\sp{2+}$-dependent and originated from capsaicin-sensitive nerve terminals. Substance P augmented morphine-evoked release of adenosine from dorsal spinal cord synatosomes similar to partial depolarization with K$\sp+.$ Nanomolar and micromolar concentrations of the selective $\mu$ opioid agonists DAMGO and PLO17 induced release of adenosine in a biphasic manner in the presence of a partial depolarization (addition of 6 mM K$\sp+$ to the Krebs medium). The $\delta$ opioid agonists DPDPE and DELT and the $\kappa$ opioid agonist U50488H had little effect on the release of adenosine except at high micromolar concentrations. DPDPE and DELT, at doses which exhibited no intrinsic effects shifted the dose response curve for $\mu$ opioid receptor-evoked adenosine release to the left in a dose-dependent manner so that release was now expressed at subnanomolar concentrations of the $\mu$ opioid receptor agonists. Simultaneous activation of $\mu$ and $\delta$ opioid receptors thus generates a synergistic release of adenosine from spinal cord synaptosomes. Release of adenosine by $\mu$ (nanomolar) and $\delta$ (micromolar) ligands is Ca$\sp{2+}$-dependent, whereas the $\kappa$ receptor ligand (micromolar) releases adenosine via a Ca$\sp{2+}$-independent mechanism. Evoked release of adenosine by nanomolar concentrations of $\mu$ opioid receptor agonists originated as adenosine per se from capsaicin-sensitive primary afferent neurons. Behavioural antinociception using the hot plate threshold test revealed that intrathecal (i.t.) administration of the $\mu$ and $\delta$ opioid receptor agonists produced dose-dependent antinociception with an order of potency of DAMGO, PLO17 $>$ morphine, DELT $>$ DPDPE. An ED$\sb{75}$ dose of morphine, DAMGO or PLO17 was dose-dependently attenuated by i.t. pretreatment 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 augmentation was dose-dependent. Adenosine-induced antinociception appears to be mediated by activation of A$\sb1$ adenosine receptors. This study demonstrates that activation of the $\mu$ receptor subtype is responsible for the opioid-induced release 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 behaviourally relevant. | en_US |
