Skip to main content
SpringerLink
Log in

Sigma-1 Receptor and Pain

  • Chapter
  • First Online:
Sigma Proteins: Evolution of the Concept of Sigma Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 244))

Abstract

There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy respect to existing therapies and/or reduce their unwanted effects. Current preclinical evidence supports the modulatory role of the sigma-1 receptor (σ1R) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists on pain of different etiology, very consistently in neuropathic pain, but also in nociceptive, inflammatory, and visceral pain. σ1R is highly expressed in different pain areas of the CNS and the periphery, particularly dorsal root ganglia (DRG), and interacts and modulates the functionality of different receptors and ion channels. Accordingly, antinociceptive effects of σ1R antagonists both acting alone and in combination with other analgesics have been reported at both central and peripheral sites. At the central level, behavioral, electrophysiological, neurochemical, and molecular findings support a role for σ1R antagonists in inhibiting augmented excitability secondary to sustained afferent input. Moreover, the involvement of σ1R in mechanisms regulating pain at the periphery has been recently confirmed. Unlike opioids, σ1R antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitivity effects (antihyperalgesic and antiallodynic) in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. These are distinctive features allowing σ1R antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abadias M, Escriche M, Vaque A, Sust M, Encina G (2013) Safety, tolerability and pharmacokinetics of single and multiple doses of a novel sigma-1 receptor antagonist in three randomized phase I studies. Br J Clin Pharmacol 75(1):103–117. doi:10.1111/j.1365-2125.2012.04333.x

    Article  CAS  PubMed  Google Scholar 

  • Almansa C, Vela JM (2014) Selective sigma-1 receptor antagonists for the treatment of pain. Future Med Chem 6(10):1179–1199. doi:10.4155/fmc.14.54

    Article  CAS  PubMed  Google Scholar 

  • Almeida TF, Roizenblatt S, Tufik S (2004) Afferent pain pathways: a neuroanatomical review. Brain Res 1000(1–2):40–56. doi:10.1016/j.brainres.2003.10.073

    Article  CAS  PubMed  Google Scholar 

  • Alonso G, Phan V, Guillemain I, Saunier M, Legrand A, Anoal M, Maurice T (2000) Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system. Neuroscience 97(1):155–170

    Article  CAS  PubMed  Google Scholar 

  • Aydar E, Palmer CP, Klyachko VA, Jackson MB (2002) The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron 34(3):399–410

    Article  CAS  PubMed  Google Scholar 

  • Balasuriya D, Stewart AP, Crottes D, Borgese F, Soriani O, Edwardson JM (2012) The sigma-1 receptor binds to the Nav1.5 voltage-gated Na+ channel with 4-fold symmetry. J Biol Chem 287(44):37021–37029. doi:10.1074/jbc.M112.382077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balasuriya D, Stewart AP, Edwardson JM (2013) The sigma-1 receptor interacts directly with GluN1 but not GluN2A in the GluN1/GluN2A NMDA receptor. J Neurosci 33(46):18219–18224. doi:10.1523/JNEUROSCI.3360-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bangaru ML, Weihrauch D, Tang QB, Zoga V, Hogan Q, Wu HE (2013) Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury. Mol Pain 9:47. doi:10.1186/1744-8069-9-47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bonin RP, Labrakakis C, Eng DG, Whissell PD, De Koninck Y, Orser BA (2011) Pharmacological enhancement of delta-subunit-containing GABA(A) receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice. Pain 152(6):1317–1326. doi:10.1016/j.pain.2011.02.011

    Article  CAS  PubMed  Google Scholar 

  • Carnally SM, Johannessen M, Henderson RM, Jackson MB, Edwardson JM (2010) Demonstration of a direct interaction between sigma-1 receptors and acid-sensing ion channels. Biophys J 98(7):1182–1191. doi:10.1016/j.bpj.2009.12.4293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cendan CM, Pujalte JM, Portillo-Salido E, Baeyens JM (2005a) Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice. Psychopharmacology (Berl) 182(4):485–493. doi:10.1007/s00213-005-0127-z

    Article  CAS  Google Scholar 

  • Cendan CM, Pujalte JM, Portillo-Salido E, Montoliu L, Baeyens JM (2005b) Formalin-induced pain is reduced in sigma(1) receptor knockout mice. Eur J Pharmacol 511(1):73–74. doi:10.1016/j.ejphar.2005.01.036

    Article  CAS  PubMed  Google Scholar 

  • Chen JF, Beilstein M, Xu YH, Turner TJ, Moratalla R, Standaert DG, Aloyo VJ, Fink JS, Schwarzschild MA (2000) Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A(2A) adenosine receptors. Neuroscience 97(1):195–204

    Article  CAS  PubMed  Google Scholar 

  • Chen JF, Moratalla R, Yu L, Martin AB, Xu K, Bastia E, Hackett E, Alberti I, Schwarzschild MA (2003) Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization. Neuropsychopharmacology 28(6):1086–1095. doi:10.1038/sj.npp.1300152

    CAS  PubMed  Google Scholar 

  • Chien CC, Pasternak GW (1993) Functional antagonism of morphine analgesia by (+)-pentazocine: evidence for an anti-opioid sigma 1 system. Eur J Pharmacol 250(1):R7–R8

    Article  CAS  PubMed  Google Scholar 

  • Chien CC, Pasternak GW (1994) Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther 271(3):1583–1590

    CAS  PubMed  Google Scholar 

  • Chien CC, Pasternak GW (1995) Sigma antagonists potentiate opioid analgesia in rats. Neurosci Lett 190(2):137–139

    Article  CAS  PubMed  Google Scholar 

  • Coderre TJ, Yashpal K, Henry JL (1994) Specific contribution of lumbar spinal mechanisms to persistent nociceptive responses in the formalin test. Neuroreport 5(11):1337–1340

    CAS  PubMed  Google Scholar 

  • D’Mello R, Dickenson AH (2008) Spinal cord mechanisms of pain. Br J Anaesth 101(1):8–16. doi:10.1093/bja/aen088

    Article  PubMed  Google Scholar 

  • de la Puente B, Nadal X, Portillo-Salido E, Sanchez-Arroyos R, Ovalle S, Palacios G, Muro A, Romero L, Entrena JM, Baeyens JM, Lopez-Garcia JA, Maldonado R, Zamanillo D, Vela JM (2009) Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain 145(3):294–303. doi:10.1016/j.pain.2009.05.013

    Article  PubMed  CAS  Google Scholar 

  • DeCoster MA, Klette KL, Knight ES, Tortella FC (1995) Sigma receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures. Brain Res 671(1):45–53

    Article  CAS  PubMed  Google Scholar 

  • Diaz JL, Cuberes R, Berrocal J, Contijoch M, Christmann U, Fernandez A, Port A, Holenz J, Buschmann H, Laggner C, Serafini MT, Burgueno J, Zamanillo D, Merlos M, Vela JM, Almansa C (2012) Synthesis and biological evaluation of the 1-arylpyrazole class of sigma(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862). J Med Chem 55(19):8211–8224. doi:10.1021/jm3007323

    Article  CAS  PubMed  Google Scholar 

  • Dickenson AH, Sullivan AF (1987) Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain 30(3):349–360

    Article  CAS  PubMed  Google Scholar 

  • Entrena JM, Cobos EJ, Nieto FR, Cendan CM, Baeyens JM, Del Pozo E (2009a) Antagonism by haloperidol and its metabolites of mechanical hypersensitivity induced by intraplantar capsaicin in mice: role of sigma-1 receptors. Psychopharmacology (Berl) 205(1):21–33. doi:10.1007/s00213-009-1513-8

    Article  CAS  Google Scholar 

  • Entrena JM, Cobos EJ, Nieto FR, Cendan CM, Gris G, Del Pozo E, Zamanillo D, Baeyens JM (2009b) Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice. Pain 143(3):252–261. doi:10.1016/j.pain.2009.03.011

    Article  CAS  PubMed  Google Scholar 

  • Flatters SJ (2015) The contribution of mitochondria to sensory processing and pain. Prog Mol Biol Transl Sci 131:119–146. doi:10.1016/bs.pmbts.2014.12.004

    Article  PubMed  Google Scholar 

  • Gao XF, Yao JJ, He YL, Hu C, Mei YA (2012) Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. PLoS One 7(11):e49384. doi:10.1371/journal.pone.0049384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garzon J, Rodriguez-Munoz M, Sanchez-Blazquez P (2012) Direct association of mu-opioid and NMDA glutamate receptors supports their cross-regulation: molecular implications for opioid tolerance. Curr Drug Abuse Rev 5(3):199–226

    Article  CAS  PubMed  Google Scholar 

  • Garzon J, Herrero-Labrador R, Rodriguez-Munoz M, Shah R, Vicente-Sanchez A, Wagner CR, Sanchez-Blazquez P (2015) HINT1 protein: a new therapeutic target to enhance opioid antinociception and block mechanical allodynia. Neuropharmacology 89:412–423. doi:10.1016/j.neuropharm.2014.10.022

    Article  CAS  PubMed  Google Scholar 

  • Gingrich JA, Hen R (2000) The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice. Curr Opin Neurobiol 10(1):146–152

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Cano R, Merlos M, Baeyens JM, Cendan CM (2013) Sigma1 receptors are involved in the visceral pain induced by intracolonic administration of capsaicin in mice. Anesthesiology 118(3):691–700. doi:10.1097/ALN.0b013e318280a60a

    Article  CAS  PubMed  Google Scholar 

  • Griesmaier E, Posod A, Gross M, Neubauer V, Wegleiter K, Hermann M, Urbanek M, Keller M, Kiechl-Kohlendorfer U (2012) Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice. Exp Neurol 237(2):388–395. doi:10.1016/j.expneurol.2012.06.030

    Article  CAS  PubMed  Google Scholar 

  • Gris G, Merlos M, Vela JM, Zamanillo D, Portillo-Salido E (2014) S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund’s adjuvant models in mice. Behav Pharmacol 25(3):226–235. doi:10.1097/FBP.0000000000000038. 35-201406000-00005 [pii]

    Article  CAS  PubMed  Google Scholar 

  • Gris G, Cobos EJ, Zamanillo D, Portillo-Salido E (2015) Sigma-1 receptor and inflammatory pain. Inflamm Res 64(6):377–381. doi:10.1007/s00011-015-0819-8

    Article  CAS  PubMed  Google Scholar 

  • Gromek KA, Suchy FP, Meddaugh HR, Wrobel RL, LaPointe LM, Chu UB, Primm JG, Ruoho AE, Senes A, Fox BG (2014) The oligomeric states of the purified sigma-1 receptor are stabilized by ligands. J Biol Chem 289(29):20333–20344. doi:10.1074/jbc.M113.537993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416(6879):396–400. doi:10.1038/416396a

    Article  CAS  PubMed  Google Scholar 

  • Guitart X, Codony X, Monroy X (2004) Sigma receptors: biology and therapeutic potential. Psychopharmacology (Berl) 174(3):301–319. doi:10.1007/s00213-004-1920-9

    Article  CAS  Google Scholar 

  • Guscott M, Bristow LJ, Hadingham K, Rosahl TW, Beer MS, Stanton JA, Bromidge F, Owens AP, Huscroft I, Myers J, Rupniak NM, Patel S, Whiting PJ, Hutson PH, Fone KC, Biello SM, Kulagowski JJ, McAllister G (2005) Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology 48(4):492–502. doi:10.1016/j.neuropharm.2004.11.015

    Article  CAS  PubMed  Google Scholar 

  • Han C, Estacion M, Huang J, Vasylyev D, Zhao P, Dib-Hajj SD, Waxman SG (2015) Human Na(v)1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J Neurophysiol 113(9):3172–3185. doi:10.1152/jn.00113.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (1996) Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A 93(15):8072–8077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi T (2015) Conversion of psychological stress into cellular stress response: roles of the sigma-1 receptor in the process. Psychiatry Clin Neurosci 69(4):179–191. doi:10.1111/pcn.12262

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Su TP (2001) Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci U S A 98(2):491–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131(3):596–610

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Maurice T, Su TP (2000) Ca(2+) signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca(2+) concentration. J Pharmacol Exp Ther 293(3):788–798

    CAS  PubMed  Google Scholar 

  • Herrera Y, Katnik C, Rodriguez JD, Hall AA, Willing A, Pennypacker KR, Cuevas J (2008) Sigma-1 receptor modulation of acid-sensing ion channel a (ASIC1a) and ASIC1a-induced Ca2+ influx in rat cortical neurons. J Pharmacol Exp Ther 327(2):491–502. doi:10.1124/jpet.108.143974

    Article  CAS  PubMed  Google Scholar 

  • Herrero JF, Laird JM, Lopez-Garcia JA (2000) Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 61(2):169–203

    Article  CAS  PubMed  Google Scholar 

  • Jamieson DG, Moss A, Kennedy M, Jones S, Nenadic G, Robertson DL, Sidders B (2014) The pain interactome: connecting pain-specific protein interactions. Pain 155(11):2243–2252. doi:10.1016/j.pain.2014.06.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johannessen M, Ramachandran S, Riemer L, Ramos-Serrano A, Ruoho AE, Jackson MB (2009) Voltage-gated sodium channel modulation by sigma-receptors in cardiac myocytes and heterologous systems. Am J Physiol Cell Physiol 296(5):C1049–C1057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johannessen M, Fontanilla D, Mavlyutov T, Ruoho AE, Jackson MB (2011) Antagonist action of progesterone at sigma-receptors in the modulation of voltage-gated sodium channels. Am J Physiol Cell Physiol 300(2):C328–C337. doi:10.1152/ajpcell.00383.2010

    Article  CAS  PubMed  Google Scholar 

  • Kekuda R, Prasad PD, Fei YJ, Leibach FH, Ganapathy V (1996) Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1). Biochem Biophys Res Commun 229(2):553–558

    Article  CAS  PubMed  Google Scholar 

  • Kim HW, Kwon YB, Roh DH, Yoon SY, Han HJ, Kim KW, Beitz AJ, Lee JH (2006) Intrathecal treatment with sigma1 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice. Br J Pharmacol 148(4):490–498. doi:10.1038/sj.bjp.0706764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HW, Roh DH, Yoon SY, Seo HS, Kwon YB, Han HJ, Kim KW, Beitz AJ, Lee JH (2008) Activation of the spinal sigma-1 receptor enhances NMDA-induced pain via PKC- and PKA-dependent phosphorylation of the NR1 subunit in mice. Br J Pharmacol 154(5):1125–1134. doi:10.1038/bjp.2008.159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim FJ, Kovalyshyn I, Burgman M, Neilan C, Chien CC, Pasternak GW (2010) Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 77(4):695–703. doi:10.1124/mol.109.057083. [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiss T (2008) Persistent Na-channels: origin and function. A review. Acta Biol Hung 59(Suppl):1–12. doi:10.1556/ABiol.59.2008.Suppl.1

    Article  PubMed  Google Scholar 

  • Kissin I (2010) The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg 110(3):780–789. doi:10.1213/ANE.0b013e3181cde882

    Article  CAS  PubMed  Google Scholar 

  • Kourrich S, Hayashi T, Chuang JY, Tsai SY, Su TP, Bonci A (2013) Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152(1–2):236–247. doi:10.1016/j.cell.2012.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon SG, Roh DH, Yoon SY, Choi SR, Choi HS, Moon JY, Kang SY, Kim HW, Han HJ, Beitz AJ, Oh SB, Lee JH (2016) Role of peripheral sigma-1 receptors in ischaemic pain: potential interactions with ASIC and P2X receptors. Eur J Pain 20(4):594–606. doi:10.1002/ejp.774

    Article  CAS  PubMed  Google Scholar 

  • Labianca R, Sarzi-Puttini P, Zuccaro SM, Cherubino P, Vellucci R, Fornasari D (2012) Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain. Clin Drug Investig 32(Suppl 1):53–63. doi:10.2165/11630080-000000000-00000

    Article  CAS  Google Scholar 

  • Lamy C, Scuvee-Moreau J, Dilly S, Liegeois JF, Seutin V (2010) The sigma agonist 1,3-di-o-tolyl-guanidine directly blocks SK channels in dopaminergic neurons and in cell lines. Eur J Pharmacol 641(1):23–28. doi:10.1016/j.ejphar.2010.05.008

    Article  CAS  PubMed  Google Scholar 

  • Lan Y, Chen Y, Cao X, Zhang J, Wang J, Xu X, Qiu Y, Zhang T, Liu X, Liu BF, Zhang G (2014a) Synthesis and biological evaluation of novel sigma-1 receptor antagonists based on pyrimidine scaffold as agents for treating neuropathic pain. J Med Chem 57(24):10404–10423. doi:10.1021/jm501207r

    Article  CAS  PubMed  Google Scholar 

  • Lan Y, Chen Y, Xu X, Qiu Y, Liu S, Liu X, Liu BF, Zhang G (2014b) Synthesis and biological evaluation of a novel sigma-1 receptor antagonist based on 3,4-dihydro-2(1H)-quinolinone scaffold as a potential analgesic. Eur J Med Chem 79:216–230. doi:10.1016/j.ejmech.2014.04.019

    Article  CAS  PubMed  Google Scholar 

  • Langa F, Codony X, Tovar V, Lavado A, Gimenez E, Cozar P, Cantero M, Dordal A, Hernandez E, Perez R, Monroy X, Zamanillo D, Guitart X, Montoliu L (2003) Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice. Eur J Neurosci 18(8):2188–2196

    Article  PubMed  Google Scholar 

  • Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10(9):895–926. doi:10.1016/j.jpain.2009.06.012

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu M, Wood JN (2011) The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med 12(Suppl 3):S93–S99. doi:10.1111/j.1526-4637.2011.01158.x

    Article  PubMed  Google Scholar 

  • Luedtke RR, Perez E, Yang SH, Liu R, Vangveravong S, Tu Z, Mach RH, Simpkins JW (2012) Neuroprotective effects of high affinity sigma1 receptor selective compounds. Brain Res 1441:17–26. doi:10.1016/j.brainres.2011.12.047

    Article  CAS  PubMed  Google Scholar 

  • Mancuso R, Olivan S, Rando A, Casas C, Osta R, Navarro X (2012) Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics 9(4):814–826. doi:10.1007/s13311-012-0140-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mardon K, Kassiou M, Donald A (1999) Effects of streptozotocin-induced diabetes on neuronal sigma receptors in the rat brain. Life Sci 65(23):PL 281–PL 286

    Article  CAS  Google Scholar 

  • Marrazzo A, Parenti C, Scavo V, Ronsisvalle S, Scoto GM, Ronsisvalle G (2006) In vivo evaluation of (+)-MR200 as a new selective sigma ligand modulating MOP, DOP and KOP supraspinal analgesia. Life Sci 78(21):2449–2453. doi:10.1016/j.lfs.2005.10.005

    Article  CAS  PubMed  Google Scholar 

  • Martina M, Turcotte ME, Halman S, Bergeron R (2007) The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus. J Physiol 578(Pt 1):143–157

    Article  CAS  PubMed  Google Scholar 

  • Mazo I, Roza C, Zamanillo D, Merlos M, Vela JM, Lopez-Garcia JA (2015) Effects of centrally acting analgesics on spinal segmental reflexes and wind-up. Eur J Pain 19(7):1012–1020. doi:10.1002/ejp.629

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ (1999) The induction of pain: an integrative review. Prog Neurobiol 57(1):1–164

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ (2002) Descending control of pain. Prog Neurobiol 66(6):355–474

    Article  CAS  PubMed  Google Scholar 

  • Min R, Di Marzo V, Mansvelder HD (2010) DAG lipase involvement in depolarization-induced suppression of inhibition: does endocannabinoid biosynthesis always meet the demand? Neuroscientist 16(6):608–613. doi:10.1177/1073858410373281

    Article  CAS  PubMed  Google Scholar 

  • Mishra AK, Mavlyutov T, Singh DR, Biener G, Yang J, Oliver JA, Ruoho A, Raicu V (2015) The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands. Biochem J 466(2):263–271. doi:10.1042/BJ20141321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monnet FP, Morin-Surun MP, Leger J, Combettes L (2003) Protein kinase C-dependent potentiation of intracellular calcium influx by sigma1 receptor agonists in rat hippocampal neurons. J Pharmacol Exp Ther 307(2):705–712. doi:10.1124/jpet.103.053447

    Article  CAS  PubMed  Google Scholar 

  • Moon JY, Roh DH, Yoon SY, Choi SR, Kwon SG, Choi HS, Kang SY, Han HJ, Beitz AJ, Oh SB, Lee JH (2014) Sigma1 receptors activate astrocytes via p38 MAPK phosphorylation leading to the development of mechanical allodynia in a mouse model of neuropathic pain. Br J Pharmacol 171(24):5881–5897. doi:10.1111/bph.12893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morin-Surun MP, Collin T, Denavit-Saubie M, Baulieu EE, Monnet FP (1999) Intracellular sigma1 receptor modulates phospholipase C and protein kinase C activities in the brainstem. Proc Natl Acad Sci U S A 96(14):8196–8199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller BH 2nd, Park Y, Daudt DR 3rd, Ma HY, Akopova I, Stankowska DL, Clark AF, Yorio T (2013) Sigma-1 receptor stimulation attenuates calcium influx through activated L-type voltage gated calcium channels in purified retinal ganglion cells. Exp Eye Res 107:21–31. doi:10.1016/j.exer.2012.11.002

    Article  CAS  PubMed  Google Scholar 

  • Ngo-Anh TJ, Bloodgood BL, Lin M, Sabatini BL, Maylie J, Adelman JP (2005) SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat Neurosci 8(5):642–649. doi:10.1038/nn1449

    Article  CAS  PubMed  Google Scholar 

  • Nieto FR, Cendan CM, Sanchez-Fernandez C, Cobos EJ, Entrena JM, Tejada MA, Zamanillo D, Vela JM, Baeyens JM (2012) Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain 13(11):1107–1121 . doi:10.1016/j.jpain.2012.08.006. S1526-5900(12)00782-1 [pii]

    Article  CAS  PubMed  Google Scholar 

  • Nieto FR, Cendan CM, Canizares FJ, Cubero MA, Vela JM, Fernandez-Segura E, Baeyens JM (2014) Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice. Mol Pain 10:11. doi:10.1186/1744-8069-10-11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH (2012) Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 64(4):939–971. doi:10.1124/pr.112.006163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Oberdorf C, Schepmann D, Vela JM, Diaz JL, Holenz J, Wunsch B (2008) Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4′-thieno[3,2-c]pyrans]. J Med Chem 51(20):6531–6537. doi:10.1021/jm8007739

    Article  CAS  PubMed  Google Scholar 

  • Ortega-Roldan JL, Ossa F, Schnell JR (2013) Characterization of the human sigma-1 receptor chaperone domain structure and binding immunoglobulin protein (BiP) interactions. J Biol Chem 288(29):21448–21457. doi:10.1074/jbc.M113.450379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osmakov DI, Andreev YA, Kozlov SA (2014) Acid-sensing ion channels and their modulators. Biochemistry 79(13):1528–1545. doi:10.1134/S0006297914130069

    CAS  PubMed  Google Scholar 

  • Pal A, Hajipour AR, Fontanilla D, Ramachandran S, Chu UB, Mavlyutov T, Ruoho AE (2007) Identification of regions of the sigma-1 receptor ligand binding site using a novel photoprobe. Mol Pharmacol 72(4):921–933

    Article  CAS  PubMed  Google Scholar 

  • Pan B, Guo Y, Kwok WM, Hogan Q, Wu HE (2014) Sigma-1 receptor antagonism restores injury-induced decrease of voltage-gated Ca2+ current in sensory neurons. J Pharmacol Exp Ther 350(2):290–300. doi:10.1124/jpet.114.214320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Parenti C, Marrazzo A, Arico G, Cantarella G, Prezzavento O, Ronsisvalle S, Scoto GM, Ronsisvalle G (2014) Effects of a selective sigma 1 antagonist compound on inflammatory pain. Inflammation 37(1):261–266. doi:10.1007/s10753-013-9736-6

    Article  CAS  PubMed  Google Scholar 

  • Pasternak GW, Kolesnikov YA, Babey AM (1995) Perspectives on the N-methyl-D-aspartate/nitric oxide cascade and opioid tolerance. Neuropsychopharmacology 13(4):309–313. doi:10.1016/0893-133X(95)00084-Q

    Article  CAS  PubMed  Google Scholar 

  • Perret D, Luo ZD (2009) Targeting voltage-gated calcium channels for neuropathic pain management. Neurotherapeutics 6(4):679–692. doi:10.1016/j.nurt.2009.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petho G, Reeh PW (2012) Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev 92(4):1699–1775. doi:10.1152/physrev.00048.2010

    Article  CAS  PubMed  Google Scholar 

  • Phan VL, Miyamoto Y, Nabeshima T, Maurice T (2005) Age-related expression of sigma1 receptors and antidepressant efficacy of a selective agonist in the senescence-accelerated (SAM) mouse. J Neurosci Res 79(4):561–572. doi:10.1002/jnr.20390

    Article  CAS  PubMed  Google Scholar 

  • Rasband MN, Park EW, Vanderah TW, Lai J, Porreca F, Trimmer JS (2001) Distinct potassium channels on pain-sensing neurons. Proc Natl Acad Sci U S A 98(23):13373–13378. doi:10.1073/pnas.231376298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richards N, McMahon SB (2013) Targeting novel peripheral mediators for the treatment of chronic pain. Br J Anaesth 111(1):46–51. doi:10.1093/bja/aet216

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Munoz M, Sanchez-Blazquez P, Herrero-Labrador R, Martinez-Murillo R, Merlos M, Vela JM, Garzon J (2015) The sigma1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control. Antioxid Redox Signal 22(10):799–818. doi:10.1089/ars.2014.5993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roh DH, Kim HW, Yoon SY, Seo HS, Kwon YB, Kim KW, Han HJ, Beitz AJ, Na HS, Lee JH (2008) Intrathecal injection of the sigma(1) receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain. Anesthesiology 109(5):879–889. doi:10.1097/ALN.0b013e3181895a83

    Article  CAS  PubMed  Google Scholar 

  • Roh DH, Choi SR, Yoon SY, Kang SY, Moon JY, Kwon SG, Han HJ, Beitz AJ, Lee JH (2011) Spinal neuronal NOS activation mediates sigma-1 receptor-induced mechanical and thermal hypersensitivity in mice: involvement of PKC-dependent GluN1 phosphorylation. Br J Pharmacol 163(8):1707–1720. doi:10.1111/j.1476-5381.2011.01316.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Romero L, Zamanillo D, Nadal X, Sanchez-Arroyos R, Rivera-Arconada I, Dordal A, Montero A, Muro A, Bura A, Segales C, Laloya M, Hernandez E, Portillo-Salido E, Escriche M, Codony X, Encina G, Burgueno J, Merlos M, Baeyens JM, Giraldo J, Lopez-Garcia JA, Maldonado R, Plata-Salaman CR, Vela JM (2012) Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization. Br J Pharmacol 166(8):2289–2306. doi:10.1111/j.1476-5381.2012.01942.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Romero L, Merlos M, Vela JM (2016) Antinociception by sigma-1 receptor antagonists: central and peripheral effects. Adv Pharmacol 75:179–215. doi:10.1016/bs.apha.2015.11.003

    Article  PubMed  Google Scholar 

  • Romero-Sandoval EA, Asbill S, Paige CA, Byrd-Glover K (2015) Peripherally restricted cannabinoids for the treatment of pain. Pharmacotherapy 35(10):917–925. doi:10.1002/phar.1642

    Article  PubMed  Google Scholar 

  • Rygh LJ, Tjolsen A, Hole K, Svendsen F (2002) Cellular memory in spinal nociceptive circuitry. Scand J Psychol 43(2):153–159

    Article  PubMed  Google Scholar 

  • Sanchez-Blazquez P, Rodriguez-Munoz M, Garzon J (2014a) The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front Pharmacol 4:169. doi:10.3389/fphar.2013.00169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sanchez-Blazquez P, Rodriguez-Munoz M, Herrero-Labrador R, Burgueno J, Zamanillo D, Garzon J (2014b) The calcium-sensitive sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases. Int J Neuropsychopharmacol 17(12):1943–1955. doi:10.1017/S1461145714000029

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Fernandez C, Nieto FR, Gonzalez-Cano R, Artacho-Cordon A, Romero L, Montilla-Garcia A, Zamanillo D, Baeyens JM, Entrena JM, Cobos EJ (2013) Potentiation of morphine-induced mechanical antinociception by sigma(1) receptor inhibition: role of peripheral sigma(1) receptors. Neuropharmacology 70:348–358 . doi:10.1016/j.neuropharm.2013.03.002. S0028-3908(13)00098-1 [pii]

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Fernandez C, Montilla-Garcia A, Gonzalez-Cano R, Nieto FR, Romero L, Artacho-Cordon A, Montes R, Fernandez-Pastor B, Merlos M, Baeyens JM, Entrena JM, Cobos EJ (2014) Modulation of peripheral mu-opioid analgesia by sigma1 receptors. J Pharmacol Exp Ther 348(1):32–45. doi:10.1124/jpet.113.208272

    Article  PubMed  CAS  Google Scholar 

  • Sandkuhler J (2000) Learning and memory in pain pathways. Pain 88(2):113–118

    Article  CAS  PubMed  Google Scholar 

  • Schetz JA, Perez E, Liu R, Chen S, Lee I, Simpkins JW (2007) A prototypical sigma-1 receptor antagonist protects against brain ischemia. Brain Res 1181:1–9. doi:10.1016/j.brainres.2007.08.068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC (2016) Crystal structure of the human sigma1 receptor. Nature 532(7600):527–530. doi:10.1038/nature17391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seth P, Leibach FH, Ganapathy V (1997) Cloning and structural analysis of the cDNA and the gene encoding the murine type 1 sigma receptor. Biochem Biophys Res Commun 241(2):535–540

    Article  CAS  PubMed  Google Scholar 

  • Shimazu S, Katsuki H, Takenaka C, Tomita M, Kume T, Kaneko S, Akaike A (2000) Sigma receptor ligands attenuate N-methyl-D-aspartate cytotoxicity in dopaminergic neurons of mesencephalic slice cultures. Eur J Pharmacol 388(2):139–146

    Article  CAS  PubMed  Google Scholar 

  • Shioda N, Ishikawa K, Tagashira H, Ishizuka T, Yawo H, Fukunaga K (2012) Expression of a truncated form of the endoplasmic reticulum chaperone protein, sigma1 receptor, promotes mitochondrial energy depletion and apoptosis. J Biol Chem 287(28):23318–23331. doi:10.1074/jbc.M112.349142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Son JS, Kwon YB (2010) Sigma-1 receptor antagonist BD1047 reduces allodynia and spinal ERK phosphorylation following chronic compression of dorsal root ganglion in rats. Korean J Physiol Pharmacol 14(6):359–364. doi:10.4196/kjpp.2010.14.6.359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE (2010) The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31(12):557–566 . doi:10.1016/j.tips.2010.08.007. S0165-6147(10)00153-7 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su TP, Su TC, Nakamura Y, Tsai SY (2016) The sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci 37(4):262–278. doi:10.1016/j.tips.2016.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tappe-Theodor A, Constantin CE, Tegeder I, Lechner SG, Langeslag M, Lepcynzsky P, Wirotanseng RI, Kurejova M, Agarwal N, Nagy G, Todd A, Wettschureck N, Offermanns S, Kress M, Lewin GR, Kuner R (2012) Galpha(q/11) signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization. Pain 153(1):184–196. doi:10.1016/j.pain.2011.10.014

    Article  CAS  PubMed  Google Scholar 

  • Tchedre KT, Huang RQ, Dibas A, Krishnamoorthy RR, Dillon GH, Yorio T (2008) Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction. Invest Ophthalmol Vis Sci 49(11):4993–5002. doi:10.1167/iovs.08-1867

    Article  PubMed  Google Scholar 

  • Tejada MA, Montilla-Garcia A, Sanchez-Fernandez C, Entrena JM, Perazzoli G, Baeyens JM, Cobos EJ (2014) Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors. Psychopharmacology (Berl) 231(19):3855–3869. doi:10.1007/s00213-014-3524-3

    Article  CAS  Google Scholar 

  • Thomas Cheng H (2010) Spinal cord mechanisms of chronic pain and clinical implications. Curr Pain Headache Rep 14(3):213–220. doi:10.1007/s11916-010-0111-0

    Article  PubMed  Google Scholar 

  • Tomohisa M, Junpei O, Aki M, Masato H, Mika F, Kazumi Y, Teruo H, Tsutomu S (2015) Possible involvement of the sigma-1 receptor chaperone in chemotherapeutic-induced neuropathic pain. Synapse 69(11):526–532. doi:10.1002/syn.21844

    Article  CAS  PubMed  Google Scholar 

  • Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand’homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JW, Wang SJ (2015) A classification of chronic pain for ICD-11. Pain 156(6):1003–1007. doi:10.1097/j.pain.0000000000000160

    PubMed  PubMed Central  Google Scholar 

  • Tsantoulas C, McMahon SB (2014) Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci 37(3):146–158. doi:10.1016/j.tins.2013.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turk DC, Wilson HD, Cahana A (2011) Treatment of chronic non-cancer pain. Lancet 377(9784):2226–2235. doi:10.1016/S0140-6736(11)60402-9

    Article  CAS  PubMed  Google Scholar 

  • Utech T, Kohler J, Buschmann H, Holenz J, Vela JM, Wunsch B (2011) Synthesis and pharmacological evaluation of a potent and selective sigma1 receptor antagonist with high antiallodynic activity. Arch Pharm (Weinheim) 344(7):415–421. doi:10.1002/ardp.201000365

    Article  CAS  Google Scholar 

  • Vaccarino AL, Chorney DA (1994) Descending modulation of central neural plasticity in the formalin pain test. Brain Res 666(1):104–108

    Article  CAS  PubMed  Google Scholar 

  • Vagnerova K, Hurn PD, Bhardwaj A, Kirsch JR (2006) Sigma 1 receptor agonists act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. Anesth Analg 103(2):430–434 (table of contents). doi:10.1213/01.ane.0000226133.85114.91

    Article  CAS  PubMed  Google Scholar 

  • Vela JM, Merlos M, Almansa C (2015) Investigational sigma-1 receptor antagonists for the treatment of pain. Expert Opin Investig Drugs 24(7):883–896. doi:10.1517/13543784.2015.1048334

    Article  CAS  PubMed  Google Scholar 

  • Vergara C, Latorre R, Marrion NV, Adelman JP (1998) Calcium-activated potassium channels. Curr Opin Neurobiol 8(3):321–329

    Article  CAS  PubMed  Google Scholar 

  • Vidal-Torres A, de la Puente B, Rocasalbas M, Tourino C, Bura SA, Fernandez-Pastor B, Romero L, Codony X, Zamanillo D, Buschmann H, Merlos M, Baeyens JM, Maldonado R, Vela JM (2013) Sigma-1 receptor antagonism as opioid adjuvant strategy: enhancement of opioid antinociception without increasing adverse effects. Eur J Pharmacol 711(1–3):63–72 . doi:10.1016/j.ejphar.2013.04.018. S0014-2999(13)00323-3 [pii]

    Article  CAS  PubMed  Google Scholar 

  • Vidal-Torres A, Fernandez-Pastor B, Carceller A, Vela JM, Merlos M, Zamanillo D (2014) Effects of the selective sigma-1 receptor antagonist S1RA on formalin-induced pain behavior and neurotransmitter release in the spinal cord in rats. J Neurochem 129(3):484–494. doi:10.1111/jnc.12648

    Article  CAS  PubMed  Google Scholar 

  • Voss LJ, Melin S, Jacobson G, Sleigh JW (2010) GABAergic compensation in connexin36 knock-out mice evident during low-magnesium seizure-like event activity. Brain Res 1360:49–55. doi:10.1016/j.brainres.2010.09.002

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Ehnert C, Brenner GJ, Woolf CJ (2006) Bradykinin and peripheral sensitization. Biol Chem 387(1):11–14. doi:10.1515/BC.2006.003

    Article  CAS  PubMed  Google Scholar 

  • Wiese C, Grosse Maestrup E, Schepmann D, Vela JM, Holenz J, Buschmann H, Wunsch B (2009) Pharmacological and metabolic characterisation of the potent sigma1 receptor ligand 1′-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine]. J Pharm Pharmacol 61(5):631–640. doi:10.1211/jpp/61.05.0012

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Yaksh TL (2011) A brief comparison of the pathophysiology of inflammatory versus neuropathic pain. Curr Opin Anaesthesiol 24(4):400–407. doi:10.1097/ACO.0b013e32834871df

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu L, Haverty PM, Mariani J, Wang Y, Shen HY, Schwarzschild MA, Weng Z, Chen JF (2005) Genetic and pharmacological inactivation of adenosine A2A receptor reveals an Egr-2-mediated transcriptional regulatory network in the mouse striatum. Physiol Genomics 23(1):89–102. doi:10.1152/physiolgenomics.00068.2005

    Article  CAS  PubMed  Google Scholar 

  • Zamanillo D, Romero L, Merlos M, Vela JM (2013) Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol 716(1–3):78–93. doi:10.1016/j.ejphar.2013.01.068

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Cuevas J (2002) Sigma receptors inhibit high-voltage-activated calcium channels in rat sympathetic and parasympathetic neurons. J Neurophysiol 87(6):2867–2879

    CAS  PubMed  Google Scholar 

  • Zhang H, Katnik C, Cuevas J (2009) Sigma receptor activation inhibits voltage-gated sodium channels in rat intracardiac ganglion neurons. Int J Physiol Pathophysiol Pharmacol 2(1):1–11

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Discovery and Preclinical Development, ESTEVE, Barcelona, Spain

    Manuel Merlos, Luz Romero, Daniel Zamanillo, Carlos Plata-Salamán & José Miguel Vela

  2. Parc Científic de Barcelona, Baldiri Reixac 4-8, 08028, Barcelona, Spain

    José Miguel Vela

Authors
  1. Manuel Merlos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luz Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Zamanillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Plata-Salamán
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José Miguel Vela
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Miguel Vela .

Editor information

Editors and Affiliations

  1. Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

    Felix J. Kim

  2. Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Gavril W. Pasternak

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Merlos, M., Romero, L., Zamanillo, D., Plata-Salamán, C., Vela, J.M. (2017). Sigma-1 Receptor and Pain. In: Kim, F., Pasternak, G. (eds) Sigma Proteins: Evolution of the Concept of Sigma Receptors. Handbook of Experimental Pharmacology, vol 244. Springer, Cham. https://doi.org/10.1007/164_2017_9

Download citation

Publish with us

Policies and ethics

Search

Navigation