In this study, we examined the anti-inflammatory mechanism by which gabapentin attenuates morphine tolerance in rats. Gabapentin enhanced the antinociceptive effect of morphine and attenuated chronic morphine tolerance when administered intrathecally with morphine in naive rats. We found that a 7-day chronic intrathecal injection of morphine increased the expression of proinflammatory cytokines and decreased interleukin-10 (IL-10) levels in the rat spinal cord. These changes were minimized when gabapentin was combined with morphine. In addition, the effects of gabapentin were reversed by coadministration of the anti-IL-10 antibody. Our findings indicate that enhancement of the antinociceptive effect of morphine by gabapentin may occur through upregulation of the anti-inflammatory cytokine IL-10 and inhibition of proinflammatory cytokines in the rat spinal cord.