Enhancement of wind-up by the combined administration of adenosine A1 receptor ligands on spinalized rats with carrageenan-induced inflammation

The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is very effective in reducing wind-up in intact but not in spinalized adult rats with carrageenan-induced inflammation, suggesting an adenosine-mediated supraspinal modulation. Since wind-up is a spinal cord mediated phenomenon but highly influenced by descending modulatory systems, especially in situations of sensitization, we assessed the possible involvement of adenosine in the modulation of wind-up. We studied the effect of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) in the presence and in the absence of the adenosine A1 receptor agonist CPA. The experiments were carried out in spinalized male Wistar rats under α-chloralose anaesthesia. Withdrawal reflexes, studied as single motor units, were activated by noxious mechanical and high-intensity repetitive electrical stimulation (wind-up). While CPA and CPT were not able to induce any change on wind-up when injected alone, the combination of the two drugs, in any order, lead to an important enhancement of wind-up. This enhancement not always paralleled an increase of responses to noxious mechanical stimulation, indicating that the effect is mainly located in the spinal cord. In addition, the enhancement of wind-up was not further increased by the administration of the opioid receptor antagonist naloxone. We conclude that the depression of the wind-up phenomenon observed in spinalized animals is, at least in part, dependent of adenosine systems and can be relieved by the combined administration of CPA and CPT.