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

Abstract We evaluated the role of σ 1 receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and σ 1 receptor knockout (σ 1 -KO) mice and selective σ 1 receptor-acting drugs. Mutation in σ 1 -KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [ 3 H](+)-pentazocine binding assays. Both wild-type and σ 1 -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 σ 1 gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar (i.pl.) 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 σ 1 -KO mice. The high-affinity and selective σ 1 antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 μg,i.pl.), yielding ED 50 (mg/kg) values of 15.80 ± 0.93, 29.31 ± 1.65 and 40.74 ± 7.20, respectively. The effects of the σ 1 antagonists were reversed by the σ 1 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 σ 1 receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.