Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: Studies with selective sigma-1 ligands and sigma-1 knockout mice

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We evaluated the role of σ1 receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and σ1 receptor knockout (σ1-KO) mice and selective σ1 receptor-acting drugs. Mutation in σ1-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [3H](+)-pentazocine binding assays. Both wild-type and σ1-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05–8 g force), ranging from innocuous to noxious, applied to the hind paw. This indicates that σ1 gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar ( administration of capsaicin induced dose-dependent mechanical allodynia in wild-type mice (markedly reducing both the threshold force necessary to induce paw withdrawal and the latency to paw withdrawal induced by a given force). In contrast, capsaicin was completely unable to induce mechanical hypersensitivity in σ1-KO mice. The high-affinity and selective σ1 antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 μg,, yielding ED50 (mg/kg) values of 15.80 ± 0.93, 29.31 ± 1.65 and 40.74 ± 7.20, respectively. The effects of the σ1 antagonists were reversed by the σ1 agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that σ1 receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.

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