Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury

Beatriz de la Puente, Xavier Nadal, Enrique Portillo-Salido, Ricard Sánchez-Arroyos, Sergio Ovalle, Gabriel Palacios, Asunción Muro, Luz Romero, José Manuel Entrena, José Manuel Baeyens, José Antonio López-García, Rafael Maldonado, Daniel Zamanillo, José Miguel Vela

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Abstract

Sigma-1 receptor (σ1R) 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 σ1R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the σ1R 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 σ1R knockout mice did not differ from wild-type mice. Baseline values obtained in σ1R 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 σ1R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking σ1R 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, σ1R 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 σ1R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to σ1R as a new potential target for drugs designed to alleviate neuropathic pain. © 2009 International Association for the Study of Pain.
Original languageEnglish
Pages (from-to)294-303
JournalPain
Volume145
Issue number3
DOIs
Publication statusPublished - 1 Oct 2009

Keywords

  • Allodynia
  • Central sensitization
  • ERK
  • Hyperalgesia
  • Neuropathic pain
  • Sigma-1 receptor
  • Spinal cord
  • Wind-up

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    Puente, B. D. L., Nadal, X., Portillo-Salido, E., Sánchez-Arroyos, R., Ovalle, S., Palacios, G., Muro, A., Romero, L., Entrena, J. M., Baeyens, J. M., López-García, J. A., Maldonado, R., Zamanillo, D., & Vela, J. M. (2009). Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain, 145(3), 294-303. https://doi.org/10.1016/j.pain.2009.05.013