Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice

Sigma-1 (σ 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 σ 1 receptor knockout (σ 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 σ 1 receptor antagonists that bind to the σ 1 receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and σ 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 σ 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 σ 1 receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that σ 1 receptors play a key role in paclitaxel-induced painful neuropathy. Perspective Antagonists of the σ 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.