8-Phenyltheophylline reverses the antinociceptive action of morphine in the periaqueductal gray

Morphine was injected into the periaqueductal gray region of the rat and 8-phenyltheophylline, an adenosine receptor antagonist, was injected intrathecally 15 or 30 min later, to determine whether supraspinally-administered morphine activated descending mechanisms to release adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. 8-Phenyltheophylline (10 μg) reversed the antinociceptive action of morphine in the hot plate but not the tail-flick test. A combination of methysergide/phentolamine (15 μg each) reversed the action of morphine in both tests. 8-Phenyltheophylline retained the ability to reverse the action of morphine in the hot plate test in rats pretreated with 6-hydroxydopamine (to induce degeneration of descending noradrenergic pathways) but reversal was no longer observed in rats pretreated with 5,7-dihydroxytryptamine (after pretreatment with desipramine, to induce degeneration of descending serotonergic pathways). These results indicate that a component of the supraspinal antinociceptive action of morphine is due to release of adenosine or nucleotide, within the spinal cord and this release is dependent on intact serotonergic pathways.