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 (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 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,i.pl.), 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.