Involvement of adenosine in the spinal antinociceptive effects of morphine and noradrenaline

Intrathecal (i.t.) pretreatment of rats with either theophylline (50 μg) or 8-phenyltheophylline (3 μg) antagonized antinociception produced by i.t. injection of morphine (0.3-3 μg) in the tailflick and hotplate tests, but had no effect on antinociception produced by i.t. injection of noradrenaline (10-30 μg). In other experiments designed to test whether morphine released adenosine from the spinal cord, adenosine release from synaptosomes was measured by high-performance liquid chromatography with fluorescence detection of etheno-adenosine. Depolarization with 24 mM K⁺ or 50 μM veratridine released 3 times as much adenosine from dorsal than from ventral spinal cord synaptosomes. K⁺ released primarily adenosine whereas veratridine released both adenosine and nucleotide(s). Morphine (1-100 μM) produced a Ca⁺⁺-dependent release of endogenous adenosine, comparable to K⁺-evoked adenosine release, which was blocked by 1 μM naltrexone. Noradrenaline (5-500 μM) produced a Ca⁺⁺-dependent release of a nucleotide which was subsequently degraded extracellularly to adenosine by ecto-5'-nucleotidase. This release was antagonized by 10 μM phentolamine and by 1 μM yohimbine. These results suggest that, within the spinal cord, morphine may act on opioid receptors to release adenosine which subsequently acts at adenosine receptors to produce spinal analgesia. Spinal analgesia produced by noradrenaline does not appear to involve adenosine release.