Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury.
Sigma-1 receptor (sigma(1)R) is expressed in key CNS areas involved in nociceptive processing but only limited information is available about its functional role. In the present study we investigated the relevance of sigma(1)R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the sigma(1)R gene were exposed to partial sciatic nerve ligation and neuropathic pain-related behaviors were investigated. To explore underlying mechanisms, spinal processing of repetitive nociceptive stimulation and expression of extracellular signal-regulated kinase (ERK) were also investigated. Sensitivity to noxious heat of homozygous sigma(1)R knockout mice did not differ from wild-type mice. Baseline values obtained in sigma(1)R knockout mice before nerve injury in the plantar, cold-plate and von Frey tests were also indistinguishable from those obtained in wild-type mice. However, cold and mechanical allodynia did not develop in sigma(1)R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking sigma(1)R showed reduced wind-up responses respect to wild-type mice, as evidenced by a reduced number of action potentials induced by trains of C-fiber intensity stimuli. In addition, in contrast to wild-type mice, sigma(1)R knockout mice did not show increased phosphorylation of ERK in the spinal cord after sciatic nerve injury. Both wind-up and ERK activation have been related to mechanisms of spinal cord sensitization. Our findings identify sigma(1)R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to sigma(1)R as a new potential target for drugs designed to alleviate neuropathic pain.
Puente
Beatriz de la
B
Department of Pharmacology, Laboratorios Esteve. Av. Mare de Déu de Montserrat, 221. 08041 Barcelona, Spain Laboratory of Neuropharmacology, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra. Doctor Aguader, 88. 08003 Barcelona, Spain Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, Universidad de Granada, Av. de Madrid 11. 18012 Granada, Spain Department of Physiology, Faculty of Medicine, Universidad de Alcalá de Henares. Alcalá de Henares, 28871 Madrid, Spain.
Nadal
Xavier
X
Portillo-Salido
Enrique
E
Sánchez-Arroyos
Ricard
R
Ovalle
Sergio
S
Palacios
Gabriel
G
Muro
Asunción
A
Romero
Luz
L
Entrena
José Manuel
JM
Baeyens
José Manuel
JM
López-García
José Antonio
JA
Maldonado
Rafael
R
Zamanillo
Daniel
D
Vela
José Miguel
JM
D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006930:Hyperalgesia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation / Q000009:adverse effects / Q000379:methods; D011930:Reaction Time / Q000235:genetics; D017480:Receptors, sigma / Q000172:deficiency / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D013116:Spinal Cord / Q000503:physiopathology*; D000097605:Sigma-1 Receptor
D048049:Extracellular Signal-Regulated MAP Kinases; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor