Pharmacology of the spinal adenosine receptor which mediates the antiallodynic action of intrathecal adenosine agonists

Abstract

The effects of intrathecally delivered adenosine agonists on allodynia induced by L5/L6 spinal nerve ligation in rats with lumbar intrathecal catheters were examined. Tactile allodynia was assessed by measuring the threshold for evoking withdrawal of the lesioned hind paw with calibrated von Frey hairs. Intrathecal administration of the A1 adenosine selective agonist, N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), produced a dose-dependent (0.3-3 nmol; ED50 = 0.6 nmol) antiallodynic action and evoked a delayed motor weakness at a dosage of 30 nmol. Intrathecal administration of the A2 adenosine selective agonist, CGS 21680 {2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride}, also produced a dose-dependent reduction in allodynia (2-40 nmol; ED50 = 15 nmol), but this effect was associated at 40 nmol after a short interval with prominent hind limb weakness. Intrathecal pretreatment with A1/A2 adenosine antagonists, caffeine (20 mumol) and 8-sulfophenyltheophylline (60 nmol), blocked antiallodynic actions of R-PIA (1 nmol) and CGS 21680 (40 nmol). Intrathecal pretreatment with the A1 adenosine-selective antagonist, 8-cyclopentyl-1,3-dimethylxanthine (3 nmol), blocked the antiallodynic effect of R-PIA (1 nmol), but even a dose as high as 10 nmol did not block the effect of CGS 21680 (40 nmol). The A2 adenosine-selective antagonist, 3, 7-dimethyl-1-propargylxanthine (3 nmol), prevented the antiallodynic effects of R-PIA (1 nmol) and CGS 21680 (40 nmol). Pretreatment with caffeine (20 mumol), 8-sulfophenyltheophylline (60 nmol) and 3,7-dimethyl-1-propargylxanthine (3 nmol) prevented the motor dysfunction induced by R-PIA (30 nmol) and CGS 21680 (40 nmol), but 8-cyclopentyl-1,3-dimethylxanthine (3 or 10 nmol) did not. Based on these effects, we hypothesize that the antiallodynic effects are mediated through the activation of spinal A1 adenosine receptors and motor dysfunction effects are mediated through A2 adenosine receptors.