Entrena José Manuel, Cobos Enrique José, Nieto Francisco Rafael, Cendán Cruz Miguel, Gris Georgia, Del Pozo Esperanza, Zamanillo Daniel, Baeyens José Manuel
Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, University of Granada, Avenida de Madrid 11, 18012 Granada, Spain Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, Armilla, 18100 Granada, Spain Laboratorios Dr. Esteve S.A., Avenida Virgen de Montserrat 221, 08041 Barcelona, Spain.
Pain. 2009 Jun;143(3):252-261. doi: 10.1016/j.pain.2009.03.011. Epub 2009 Apr 17.
We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(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 sigma(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 sigma(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 sigma(1)-KO mice. The high-affinity and selective sigma(1) antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 microg,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 sigma(1) antagonists were reversed by the sigma(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 sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.
我们使用野生型和σ1受体基因敲除（σ1-KO）小鼠以及选择性作用于σ1受体的药物，评估了σ1受体在辣椒素诱导的机械性超敏反应以及点状机械刺激诱导的伤害性疼痛中的作用。通过对基因组DNA进行PCR分析，并在蛋白质水平上通过³H-喷他佐辛结合试验，证实了σ1-KO小鼠中的突变。未用辣椒素处理的野生型和σ1-KO小鼠对施加于后爪的不同强度机械刺激（0.05-8克力）（从无害到有害）均表现出相似的反应。这表明σ1基因失活不会改变点状机械刺激的感知。足底内（i.pl.）注射辣椒素在野生型小鼠中诱导出剂量依赖性的机械性异常性疼痛（显著降低诱导爪退缩所需的阈值力以及给定力诱导的爪退缩潜伏期）。相比之下，辣椒素在σ1-KO小鼠中完全无法诱导机械性超敏反应。皮下（s.c.）注射高亲和力和选择性σ1拮抗剂BD-1063、BD-1047和NE-100，剂量依赖性地抑制了辣椒素（1微克，i.pl.）诱导的机械性异常性疼痛，产生的ED50（毫克/千克）值分别为15.80±0.93、29.31±1.65和40.74±7.20。σ1激动剂PRE-084（32毫克/千克，s.c.）可逆转σ1拮抗剂的作用。所测试的药物均未改变未致敏动物中疼痛性机械点状刺激（4克力）诱导的反应。这些结果表明，σ1受体对于辣椒素诱导的机械性超敏反应至关重要，但不参与机械性伤害性疼痛。
