Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord

Abstract

Intrathecal (i.t.) coadministration of calcium (Ca 2+), 50 μg potentiates the spinal antinociceptive action of morphine and noradrenaline (NA) but not cyclohexyladenosine, 5′-N-ethylcar☐amido adenosine or 5-hydroxytryptamine in the rat tail flick test. This dose of Ca 2+ has no intrinsic effect in this test. Higher doses of Ca 2+ (200–400 μg) produce antinociception in the tail flick and hot plate tests, which is completely blocked by pretreatment with the adenosine receptor antagonists theophylline, 50 μg and 8-phenyltheophylline, 3 μg. 8-Phenyltheophylline also eliminates potentiation of the antinociceptive action of NA by 50 μg Ca 2+. The intrinsic antinociceptive effect of Ca 2+ is blocked by i.t. pretreatment with the neurotoxins capsaicin, 50 μg and 6-hydroxydopamine, 50 μg but not 5,7-dihydroxytryptamine, 50 μg. Antinociception also is blocked by pretreatment with phentolamine but not by methysergide. These results suggest that the antinociceptive action of high doses of Ca 2+ is due to release of adenosine (or a nucleotide is metabolized to adenosine) from the spinal cord. At lower doses, the release of adenosine is insufficient to cause antinociception, but potentiates the action of NA. Adenosine appears to originate from capsaicin-sensitive small diameter primary afferent nerve terminals. A subsequent interaction of adenosine with spinal adrenergic receptors contributes to antinociception.