Roles of adenosine receptor subtypes on the antinociceptive effect of sildenafil in rat spinal cord

We recently found that the antinociceptive effects produced by intrathecal administration of sildenafil, a phosphodiesterase 5 inhibitor, were reversed by a nonspecific adenosine receptor antagonist, suggesting that adenosine receptors are involved in sildenafil-induced antinociception. Four adenosine receptor subtypes have been identified: A1, A2A, A2B, and A3. We examined the involvement of spinal adenosine receptor subtypes in the antinociceptive effects of intrathecal sildenafil. Intrathecal catheters were implanted in male SD rats, and nociception was assessed using the formalin test, which consisted of a subcutaneous injection of 50 μl of 5% formalin solution into the hind paw. We examined the effects of an adenosine A1 receptor antagonist (CPT), an adenosine A2A receptor antagonist (CSC), an adenosine A2B receptor antagonist (alloxazine), and an adenosine A3 receptor antagonist (MRS 1220) on sildenafil-induced antinociception. Intrathecal sildenafil suppressed formalin-induced flinching during phases 1 and 2 of the test in a dose-dependent manner. Intrathecal CPT, CSC, alloxazine, and MRS 1220 all suppressed the antinociceptive effects of sildenafil during both phases of the formalin test. These results suggest that sildenafil is an effective treatment for acute pain and the facilitated pain state at the spinal level. Additionally, spinal adenosine A1, A2A, A2B, and A3 receptors may play a role in sildenafil-induced antinociception.