Role of Sigma-1 Receptors in Paclitaxel-Induced Neuropathic Pain in Mice

Sigma-1 (sigma(1)) receptors play a role in different types of pain and in central sensitization mechanisms; however, it is unknown whether they are involved in chemotherapy-induced neuropathic pain. We compared the ability of paclitaxel to induce cold (acetone test) and mechanical (electronic Von Frey test) allodynia in wild-type (WT) and sigma(1) receptor knockout (sigma(1)-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063 (16-64 mg/kg, subcutaneously) and S1RA (32-128 mg/kg, subcutaneously), 2 selective sigma(1) receptor antagonists that bind to the sigma(1) receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and sigma(1)-KO mice not treated with paclitaxel; however, treatment with paclitaxel (2 mg/kg, intraperitoneally, once per day during 5 consecutive days) produced cold and mechanical allodynia and an increase in spinal cord diphosphorylated extracellular signal-regulated kinase (pERK) in WT but not in sigma(1)-KO mice. The administration of BD-1063 or S1RA 30 minutes before each paclitaxel dose prevented the development of cold and mechanical allodynia in WT mice. Moreover, the acute administration of both sigma(1) receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that sigma(1) receptors play a key role in paclitaxel-induced painful neuropathy. Perspective: Antagonists of the sigma(1) receptor may have therapeutic value for the treatment and/or prevention of paclitaxel-induced neuropathic pain. This possibility is especially interesting in the context of chemotherapy-induced neuropathy, where the onset of nerve damage is predictable and preventive treatment could be administered. (C) 2012 by the American Pain Society