Inflammation Research

, Volume 64, Issue 6, pp 377–381 | Cite as

Sigma-1 receptor and inflammatory pain

  • Georgia Gris
  • Enrique José Cobos
  • Daniel Zamanillo
  • Enrique Portillo-Salido



The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain.


Recent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary.


Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.


Sigma-1 receptor Inflammatory pain Analgesic Arthritis Carrageenan Complete Freund’s adjuvant 



Enrique J Cobos was partially supported by Grant SAF2013-47481-P from the Spanish Government (Madrid, Spain), FEDER funds, Grant CTS109 from the Junta de Andalucía (Seville, Spain), and the Research Program of the University of Granada.


  1. 1.
    Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE. The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci. 2010;31:557–66.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Zamanillo D, Romero L, Merlos M, Vela JM. Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol. 2013;716:78–93.CrossRefPubMedGoogle Scholar
  3. 3.
    Wolfe SA Jr, Culp SG, De Souza EB. Sigma-receptors in endocrine organs: identification, characterization, and autoradiographic localization in rat pituitary, adrenal, testis, and ovary. Endocrinology. 1989;124:1160–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Alonso G, Phan V, Guillemain I, Saunier M, Legrand A, Anoal M, Maurice T. Immunocytochemical localization of the sigma-1 receptor in the adult rat central nervous system. Neuroscience. 2000;97:155–70.CrossRefPubMedGoogle Scholar
  5. 5.
    Kitaichi K, Chabot JG, Moebius FF, Flandorfer A, Glossmann H, Quirion R. Expression of the purported sigma-1 (sigma(1)) receptor in the mammalian brain and its possible relevance in deficits induced by antagonism of the NMDA receptor complex as revealed using an antisense strategy. J Chem Neuroanat. 2000;20:375–87.CrossRefPubMedGoogle Scholar
  6. 6.
    Chien CC, Pasternak GW. Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther. 1994;271:1583–90.PubMedGoogle Scholar
  7. 7.
    Gris G, Merlos M, Vela JM, Zamanillo D, Portillo-Salido E. S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund’s adjuvant models in mice. Behav Pharmacol. 2014;25:226–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Parenti C, Marrazzo A, Aricò G, Cantarella G, Prezzavento O, Ronsisvalle S, Scoto GM, Ronsisvalle G. Effects of a selective sigma-1 antagonist compound on inflammatory pain. Inflammation. 2014;37:261–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Parenti C, Marrazzo A, Aricò G, Parenti R, Pasquinucci L, Ronsisvalle S, Ronsisvalle G, Scoto GM. The antagonistic effect of the sigma 1 receptor ligand (+)-MR200 on persistent pain induced by inflammation. Inflamm Res. 2014;63:231–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Tejada MA, Montilla-García A, Sánchez-Fernández C, Entrena JM, Perazzoli G, Baeyens JM, Cobos EJ. Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors. Psychopharmacology. 2014;31:3855–69.CrossRefGoogle Scholar
  11. 11.
    Cendán CM, Pujalte JM, Portillo-Salido E, Montoliu L, Baeyens JM. Formalin-induced pain is reduced in sigma-1 receptor knockout mice. Eur J Pharmacol. 2005;511:73–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Entrena JM, Cobos EJ, Nieto FR, Cendán CM, Gris G, Del Pozo E, Zamanillo D, Baeyens JM. Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice. Pain. 2009;143:252–61.CrossRefPubMedGoogle Scholar
  13. 13.
    De la Puente B, Nadal X, Portillo-Salido E, Sánchez-Arroyos R, Ovalle S, Palacios G, Muro A, Romero L, Entrena JM, Baeyens JM, López-García JA, Maldonado R, Zamanillo D, Vela JM. Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain. 2009;145:294–303.CrossRefPubMedGoogle Scholar
  14. 14.
    Nieto FR, Cendán CM, Sánchez-Fernández C, Cobos EJ, Entrena JM, Tejada MA, Zamanillo D, Vela JM, Baeyens JM. Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain. 2012;13:1107–21.CrossRefPubMedGoogle Scholar
  15. 15.
    Cobos EJ, Portillo-Salido E. “Bedside-to-bench” behavioral outcomes in animal models of pain: beyond the evaluation of reflexes. Curr Neuropharmacol. 2013;11:560–91.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Zamanillo D, Portillo-Salido E, Vela JM, Romero L. Sigma 1 Receptor Chaperone: pharmacology and therapeutic perspectives. In: Botana M, Loza M, editors. Therapeutic targets: modulation, inhibition, and activation. Hoboken: John Wiley & Sons Inc.; 2012. p. 225–78.CrossRefGoogle Scholar
  17. 17.
    Almansa C, Vela JM. Selective sigma-1 receptor antagonists for the treatment of pain. Future Med Chem. 2014;6:1179–99.CrossRefPubMedGoogle Scholar
  18. 18.
    Romero L, Zamanillo D, Nadal X, Sánchez-Arroyos R, Rivera-Arconada I, Dordal A, Montero A, Muro A, Bura A, Segalés C, Laloya M, Hernández E, Portillo-Salido E, Escriche M, Codony X, Encina G, Burgueño J, Merlos M, Baeyens JM, Giraldo J, López-García JA, Maldonado R, Plata-Salamán CR, Vela JM. Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization. Br J Pharmacol. 2012;166:2289–306.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Sánchez-Fernández C, Montilla-García Á, González-Cano R, Nieto FR, Romero L, Artacho-Cordón A, Montes R, Fernández-Pastor B, Merlos M, Baeyens JM, Entrena JM, Cobos EJ. Modulation of peripheral μ-opioid analgesia by σ1 receptors. J Pharmacol Exp Ther. 2014;348:32–45.CrossRefPubMedGoogle Scholar
  20. 20.
    Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain. 1993;52:127–36.CrossRefPubMedGoogle Scholar
  21. 21.
    Hayashi T, Maurice T, Su TP. Ca(2+) signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca(2+) concentration. J Pharmacol Exp Ther. 2000;293:788–98.PubMedGoogle Scholar
  22. 22.
    Roh DH, Choi SR, Yoon SY, Kang SY, Moon JY, Kwon SG, Han HJ, Beitz AJ, Lee JH. Spinal neuronal NOS activation mediates sigma-1 receptor-induced mechanical and thermal hypersensitivity in mice: involvement of PKC-dependent GluN1 phosphorylation. Br J Pharmacol. 2011;163:1707–20.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Karim F, Wang CC. Gereau RW 4th Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice. J Neurosci. 2001;21:3771–9.PubMedGoogle Scholar
  24. 24.
    Galan A, Lopez-Garcia JA, Cervero F, Laird JM. Activation of spinal extracellular signaling-regulated kinase-1 and -2 by intraplantar carrageenan in rodents. Neurosci Lett. 2002;322:37–40.CrossRefPubMedGoogle Scholar
  25. 25.
    Ji RR, Befort K, Brenner GJ, Woolf CJ. ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci. 2002;22:478–85.PubMedGoogle Scholar
  26. 26.
    Adwanikar H, Karim F, Gereau RW 4th. Inflammation persistently enhances nocifensive behaviors mediated by spinal group I mGluRs through sustained ERK activation. Pain. 2004;111:125–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Cruz CD, Neto FL, Castro-Lopes J, McMahon SB, Cruz F. Inhibition of ERK phosphorylation decreases nociceptive behaviour in monoarthritic rats. Pain. 2005;116:411–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Barrett JE. The pain of pain: challenges of animal behavior models. Eur J Pharmacol. 2015. doi: 10.1016/S0014-2999(15)00017-5.PubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Georgia Gris
    • 1
  • Enrique José Cobos
    • 2
  • Daniel Zamanillo
    • 1
  • Enrique Portillo-Salido
    • 1
  1. 1.Drug Discovery and Preclinical Development, ESTEVE, Baldiri ReixachBarcelonaSpain
  2. 2.Department of Pharmacology and Institute of Neuroscience, Faculty of MedicineUniversity of GranadaGranadaSpain

Personalised recommendations