Antinociception by adenosine analogs and an adenosine kinase inhibitor: dependence on formalin concentration

Spinal administration of adenosine analogs and an adenosine kinase inhibitor produces antinociception in thermal threshold tests. In the present study, we determined the effects of N⁶-cyclohexyladenosine (adenosine A₁ receptor selective), 2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethyl-carboxamidoadenosine (CGS-21680) (adenosine A_2A receptor selective), and 5′-N-ethylcarboxamidoadenosine (NECA) (non-selective), on formalin induced nociceptive responses (flinching/lifting and licking/biting) using two concentrations of formalin (2% and 5%). We also examined the antinociceptive effects of 5′-amino-5′-deoxyadenosine, an adenosine kinase inhibitor, and deoxycoformycin, an adenosine deaminase inhibitor, under these conditions. Adenosine A₁ receptor agonists, but not the A_2A selective agent, produced significant antinociception, as did 5′-amino-5′-deoxyadenosine, but not deoxycoformycin. The extent of antinociception produced was greater with the lower stimulus intensity. The effects of NECA and 5′-amino-5′-deoxyadenosine were inhibited by caffeine, indicating the involvement of cell surface adenosine receptors in their actions. We conclude (a) that the adenosine A₁, but not the A_2A, receptor is involved in spinally mediated antinociception, (b) that adenosine kinase is more important than adenosine deaminase in regulating endogenous adenosine levels in the spinal cord, and (c) that stimulus intensity is an important determinant of the efficacy of purines in the spinal cord.