Caffeine prevents antihyperalgesic effect of gabapentin in an animal model of CRPS‐I: evidence for the involvement of spinal adenosine A1 receptor

This study was designed to determine whether 3 weeks of gabapentin treatment is effective in alleviating neuropathic pain‐like behavior in animal models of complex regional pain syndrome type‐I and partial sciatic nerve ligation (PSNL). We investigated the contribution of adenosine subtypes to the antihyperalgesic effect of gabapentin by examining the effect of caffeine, a non‐selective adenosine A1 and A2 receptor antagonist or 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX), a selective adenosine A1 subtype receptor antagonist on this effect. Neuropathic pain was produced by unilateral prolonged hind paw ischemia and reperfusion (I/R) or PSNL procedures which resulted in stimulus‐evoked mechanical hyperalgesia. After procedures, animals received gabapentin (10, 30, or 100 mg/kg intraperitoneal, respectively), caffeine (10 mg/kg intraperitoneal or 150 nmol intrathecally) or DPCPX (3 µg intrathecally) alone or in combination. Mice were tested for tactile mechanical hyperalgesia at 1, 2, and 3 weeks following procedures. Gabapentin produced dose‐related inhibition of mechanical hyperalgesia over a 3‐week period, and this effect was blocked by concomitant caffeine or DPCPX administration 1 week after injuries. The results of this study demonstrated that the mechanism through which gabapentin produces its effect may involve the activation of adenosine A1 subtype receptor.