Intracerebroventricular morphine releases adenosine and adenosine 3',5'-cyclic monophosphate from the spinal cord via a serotonergic mechanism.

Intracerebroventricular (i.c.v.) administration of morphine produces antinociception which is antagonized by intrathecal (i.t.) injection of adenosine receptor antagonists, suggesting that adenosine release from the spinal cord may partially mediate antinociception produced by supraspinal morphine. In the present study we have examined this hypothesis directly. Administration of 40 nmol of morphine i.c.v. acutely to rats increased tail-flick and hot-plate nociceptive latencies. This antinociception was antagonized by i.t. theophylline (12 nmol) and 8-phenyltheophylline (1.2 and 12 nmol), but was potentiated by a high dose of theophylline (120 nmol). The same dose of i.c.v. morphine increased the release of adenosine into i.t. perfusates by 40 to 60% above basal release values, and also released a nucleotide which was identified as cyclic AMP by using high performance liquid chromatography. This release of adenosine and cyclic AMP was reduced after i.t. pretreatment with 5,7-dihydroxytryptamine (100 micrograms) but not 6-hydroxydopamine (100 micrograms). Spinal release of purines induced by i.c.v. morphine also was reduced by i.t. perfusion with 50 microM methysergide whereas 50 microM phentolamine had no effect. These data suggest that i.c.v. morphine activates descending serotonergic pathways to release purines from the spinal cord, and that such release is secondary to release of 5-hydroxytryptamine. Extracellular adenosine may contribute significantly to antinociception produced by supraspinal morphine.