5-Hydroxytryptamine releases adenosine and cyclic AMP from primary afferent nerve terminals in the spinal cord in vivo.

5-Hydroxytryptamine (5-HT) releases a purine nucleotide, which is subsequently converted to adenosine, from primary afferent nerve terminals in vitro. This release may mediate spinal antinociception by 5-HT. In the present study, we have investigated whether release also occurs from the spinal cord in vivo using an intrathecal perfusion system in rats. Adenosine was quantitated using high performance liquid chromatography (HPLC) with fluorescence detection. Following perfusion of the spinal cord with 50 and 500 microM 5-HT, a 35-50% increase in the release of endogenous adenosine was observed. This release was completely blocked by 50 microM methysergide, and by intrathecal injection with 100 micrograms capsaicin 5-8 days prior to release experiments. Intrathecal perfusion with 50 and 500 microM 5-HT also released a nucleotide which eluted from the HPLC column at a retention time identical to that of cyclic AMP standards, and was reduced following incubation with cyclic AMP phosphodiesterase. This release of cyclic AMP also was eliminated following intrathecal pretreatment with capsaicin. In contrast to 5-HT, noradrenaline (NA, 500 microM and 5 mM) did not release adenosine or cyclic AMP from the intact spinal cord. These data demonstrate that release of nucleotide, probably cyclic AMP, and subsequent metabolism to adenosine, can be induced by 5-HT but not NA in vivo. This strengthens the hypothesis that release of adenosine from the spinal cord may mediate antinociception by intrathecal 5-HT but not NA.