Skip to main content
SpringerLink
Log in

Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Sigma-1 (σ1) receptor inhibition ameliorates neuropathic pain by inhibiting central sensitization. However, it is unknown whether σ1 receptor inhibition also decreases inflammatory hyperalgesia, or whether peripheral σ1 receptors are involved in this process.

Objective

The purpose of this study was to determine the role of σ1 receptors in carrageenan-induced inflammatory hyperalgesia, particularly at the inflammation site.

Results

The subcutaneous (s.c.) administration of the selective σ1 antagonists BD-1063 and S1RA to wild-type mice dose-dependently and fully reversed inflammatory mechanical (paw pressure) and thermal (radiant heat) hyperalgesia. These antihyperalgesic effects were abolished by the s.c. administration of the σ1 agonist PRE-084 and also by the intraplantar (i.pl.) administration of this compound in the inflamed paw, suggesting that blockade of peripheral σ1 receptors in the inflamed site is involved in the antihyperalgesic effects induced by σ1 antagonists. In fact, the i.pl. administration of σ1 antagonists in the inflamed paw (but not in the contralateral paw) was sufficient to completely reverse inflammatory hyperalgesia. σ1 knockout (σ1-KO) mice did not develop mechanical hyperalgesia but developed thermal hypersensitivity; however, the s.c. administration of BD-1063 or S1RA had no effect on thermal hyperalgesia in σ1-KO mice, supporting on-target mechanisms for the effects of both drugs. The antiedematous effects of σ1 inhibition do not account for the decreased hyperalgesia, since carrageenan-induced edema was unaffected by σ1 knockout or systemic σ1 pharmacological antagonism.

Conclusions

σ1 receptors play a major role in inflammatory hyperalgesia. Targeting σ1 receptors in the inflamed tissue may be useful for the treatment of inflammatory pain.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Alonso G, Phan V, Guillemain I, Saunier M, Legrand A, Anoal M, Maurice T (2000) Immunocytochemical localization of the sigma1 receptor in the adult rat central nervous system. Neuroscience 97:155–170

    Article  PubMed  CAS  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

    Article  PubMed  PubMed Central  Google Scholar 

  • Bonin RP, Labrakakis C, Eng DG, Whissell PD, De Koninck Y, Orser BA (2011) Pharmacological enhancement of δ-subunit-containing GABAA receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice. Pain 152:1317–1326

    Article  PubMed  CAS  Google Scholar 

  • Cendán CM, Pujalte JM, Portillo-Salido E, Baeyens JM (2005a) Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice. Psychopharmacology 182:485–493

    Article  PubMed  Google Scholar 

  • Cendán CM, Pujalte JM, Portillo-Salido E, Montoliu L, Baeyens JM (2005b) Formalin-induced pain is reduced in σ1 receptor knockout mice. Eur J Pharmacol 511:73–74

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns (4,5) P2-mediated inhibition. Nature 411:957–962

    Article  PubMed  CAS  Google Scholar 

  • Cobos EJ, Portillo-Salido E (2013) “Bedside-to-bench” behavioral outcomes in animal models of pain: beyond the evaluation of reflexes. Curr Neuropharmacol 11:560–591

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cobos EJ, Entrena JM, Nieto FR, Cendán CM, Del Pozo E (2008) Pharmacology and therapeutic potential of σ1 receptor ligands. Curr Neuropharmacol 6:344–366

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 (2009) Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain 145:294–303

    Article  PubMed  Google Scholar 

  • Díaz JL, Cuberes R, Berrocal J, Contijoch M, Christmann U, Fernández A, Port A, Holenz J, Buschmann H, Laggner C, Serafini MT, Burgueño J, Zamanillo D, Merlos M, Vela JM, Almansa C (2012) Synthesis and biological evaluation of the 1-arylpyrazole class of σ1 receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy] ethyl} morpholine (S1RA, E-52862). J Med Chem 55:8211–8224

    Article  PubMed  Google Scholar 

  • Dubin AE, Patapoutian A (2010) Nociceptors: the sensors of the pain pathway. J Clin Invest 120:3760–3772

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Entrena JM, Cobos EJ, Nieto FR, Cendán CM, Baeyens JM, Del Pozo E (2009b) Antagonism by haloperidol and its metabolites of mechanical hypersensitivity induced by intraplantar capsaicin in mice: role of sigma-1 receptors. Psychopharmacology 205:21–33

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • González-Cano R, Merlos M, Baeyens JM, Cendán CM (2013) σ1 receptors are involved in the visceral pain induced by intracolonic administration of capsaicin in mice. Anesthesiology 118:691–700

    Article  PubMed  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 48:492–502

    Article  PubMed  CAS  Google Scholar 

  • Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88

    Article  PubMed  CAS  Google Scholar 

  • Hayashi T, Su TP (2004) Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18:269–284

    Article  PubMed  CAS  Google Scholar 

  • Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596–610

    Article  PubMed  CAS  Google Scholar 

  • Hayashi T, Maurice T, Su TP (2000) Ca2+ signaling via σ1-receptors: novel regulatory mechanism affecting intracellular Ca2+ concentration. J Pharmacol Exp Ther 293:788–798

    PubMed  CAS  Google Scholar 

  • Hong W, Nuwayhid SJ, Werling LL (2004) Modulation of bradykinin-induced calcium changes in SH-SY5Y cells by neurosteroids and sigma receptor ligands via a shared mechanism. Synapse 54:102–110

    Article  PubMed  CAS  Google Scholar 

  • Ji RR (2004) Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases. Curr Drug Targets Inflamm Allergy 3:299–303

    Article  PubMed  CAS  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 148:490–498

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kitaichi K, Chabot JG, Moebius FF, Flandorfer A, Glossmann H, Quirion R (2000) Expression of the purported sigma1 (σ1) 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 20:75–387

    Article  Google Scholar 

  • Kourrich S, Su TP, Fujimoto M, Bonci A (2012) The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci 35:762–771

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Marrazzo A, Cobos EJ, Parenti C, Aricò G, Marrazzo G, Ronsisvalle S, Pasquinucci L, Prezzavento O, Colabufo NA, Contino M, González LG, Scoto GM, Ronsisvalle G (2011) Novel potent and selective σ ligands: evaluation of their agonist and antagonist properties. J Med Chem 54:3669–3673

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto RR, Bowen WD, Tom MA, Vo VN, Truong DD, De Costa BR (1995) Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur J Pharmacol 280:301–310

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto RR, McCracken KA, Friedman MJ, Pouw B, De Costa BR, Bowen WD (2001) Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice. Eur J Pharmacol 419:163–174

    Article  PubMed  CAS  Google Scholar 

  • Mei J, Pasternak GW (2002) σ1 receptor modulation of opioid analgesia in the mouse. J Pharmacol Exp Ther 300:1070–1074

    Article  PubMed  CAS  Google Scholar 

  • Mei J, Pasternak GW (2007) Modulation of brainstem opiate analgesia in the rat by sigma 1 receptors: a microinjection study. J Pharmacol Exp Ther 322:1278–1285

    Article  PubMed  CAS  Google Scholar 

  • Menéndez L, Lastra A, Meana A, Hidalgo A, Baamonde A (2005) Analgesic effects of loperamide in bone cancer pain in mice. Pharmacol Biochem Behav 81:114–121

    Article  PubMed  Google Scholar 

  • Nakamura M, Ferreira SH (1988) Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances. Eur J Pharmacol 146:223–228

    Article  PubMed  CAS  Google Scholar 

  • Nieto FR, Entrena JM, Cendán CM, Del Pozo E, Vela JM, Baeyens JM (2008) Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice. Pain 137:520–531

    Article  PubMed  CAS  Google Scholar 

  • Nieto FR, Cendán CM, Sánchez-Fernández 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 13:1107–1121

    Article  PubMed  CAS  Google Scholar 

  • Park H, Kim YH, Chang HW, Kim HP (2008) Anti-inflammatory activity of the synthetic C-C biflavonoids. J Pharm Pharmacol 58:1661–1667

    Article  Google Scholar 

  • Patapoutian A, Tate S, Woolf CJ (2009) Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8:55–68

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Petrus M, Peier AM, Bandell M, Hwang SW, Huynh T, Olney N, Jegla T, Patapoutian A (2007) A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol Pain 3:40

    Article  PubMed  PubMed Central  Google Scholar 

  • Posadas I, Bucci M, Roviezzo F, Rossi A, Parente L, Sautebin L, Cirino G (2004) Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression. Br J Pharmacol 142:331–338

    Article  PubMed  CAS  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 σ1 receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain. Anesthesiology 109:879–889

    Article  PubMed  CAS  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 163:1707–1720

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 (2012) Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization. Br J Pharmacol 166:2289–2306

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sánchez-Fernández C, Nieto FR, González-Cano R, Artacho-Cordón A, Romero L, Montilla-García Á, Zamanillo D, Baeyens JM, Entrena JM, Cobos EJ (2013) Potentiation of morphine-induced mechanical antinociception by σ1 receptor inhibition: role of peripheral σ1 receptors. Neuropharmacology 70:348–358

    Article  PubMed  Google Scholar 

  • Sánchez-Fernández C, Montilla-García A, González-Cano R, Nieto FR, Romero L, Artacho-Cordón A, Montes R, Fernández-Pastor B, Merlos M, Baeyens JM, Entrena JM, Cobos EJ (2014) Modulation of μ-opioid analgesia by peripheral σ1 receptors. J Pharmacol Exp Ther 348:32–45

    Article  PubMed  Google Scholar 

  • Sandkühler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758

    Article  PubMed  Google Scholar 

  • Scholz J, Woolf CJ (2002) Can we conquer pain? Nat Neurosci 5:1062–1067

    Article  PubMed  CAS  Google Scholar 

  • Vidal-Torres A, de la Puente B, Rocasalbas M, Touriño C, Andreea Bura S, Fernández-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 711:63–72

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Ehnerta C, Brenner GJ, Woolf C (2006) Bradykinin and peripheral sensitization. Biol Chem 387:11–14

    PubMed  CAS  Google Scholar 

  • Woolf CJ (2004) Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 140:441–451

    Article  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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

M.A. Tejada was supported by a predoctoral grant from the University of Granada. E.J. Cobos was supported by the Research Program of the University of Granada. This research was done in partial fulfillment of the requirements for the doctoral thesis of M.A. Tejada. The authors thank K. Shashok for revising the English style of the manuscript.

Funding

This study was partially supported by the Spanish Ministry of Education and Science (MEC) [grant SAF2010-15343], Junta de Andalucía [grant CTS 109], CEI BioTic Granada, FEDER funds, Laboratorios Esteve, and The Center for Industrial Technological Development (Spanish Government) [Genius Pharma project].

Conflict of interest

All authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, University of Granada, Avenida de Madrid 11, 18012, Granada, Spain

    M. A. Tejada, A. Montilla-García, C. Sánchez-Fernández, J. M. Baeyens & E. J. Cobos

  2. Institute of Neuroscience, Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100, Armilla, Granada, Spain

    M. A. Tejada, A. Montilla-García, C. Sánchez-Fernández, J. M. Entrena, J. M. Baeyens & E. J. Cobos

  3. Animal Behavior Research Unit, Scientific Instrumentation Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100, Armilla, Granada, Spain

    J. M. Entrena

  4. Department of Anatomy and Embryology, School of Medicine, University of Granada, Avenida de Madrid 11, 18012, Granada, Spain

    G. Perazzoli

  5. Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100, Armilla, Granada, Spain

    G. Perazzoli

Authors
  1. M. A. Tejada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Montilla-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Sánchez-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. M. Entrena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Perazzoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. M. Baeyens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. J. Cobos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. J. Cobos.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tejada, M.A., Montilla-García, A., Sánchez-Fernández, C. et al. Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors. Psychopharmacology 231, 3855–3869 (2014). https://doi.org/10.1007/s00213-014-3524-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3524-3

Keywords

Search

Navigation