Chronic pain affects approximately one-third of Americans, and resistance to analgesics such as the opiates is a clinical problem in need of new therapeutic strategies. Recent studies have suggested that pathogenic processes in the spinal cord have a role in the development of opiate tolerance. Specifically, nitric oxide and peroxinitrite production and neuronal apoptosis have been linked to neuroimmune activation of glial cells and proinflammatory cytokine production during the development of long-term morphine treatment and development of tolerance. In this issue, Ndengele et al., describe a detailed mechanistic work on the role of ceramides in the mechanism of morphine tolerance. The authors examined the role of ceramide on the development of tolerance using inhibitors of de novo and sphingomyelinase pathways of ceramide biosynthesis. For example, an inhibitor of ceramide synthase blocked tolerance induction and nitration-dependent inactivation of manganese superoxide dismutase. The authors showed that nuclear factor κB activation is involved in tolerance, presumably through ceramide/peroxynitrite pathways, and that the ceramide synthase inhibitor also blocked these effects. The results define for the first time a role for ceramide in the development of antinociceptive tolerance and suggest that inhibitors of ceramide metabolism might be useful in the management of pain.
See article at J Pharmacol Exp Ther 2009, 329:64-75.
- The American Society for Pharmacology and Experimental Therapeutics