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

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.

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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.

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Correspondence to E. J. Cobos.

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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

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Keywords

  • Sigma-1 receptors
  • Inflammatory pain
  • Carrageenan
  • Hyperalgesia
  • BD-1063
  • S1RA
  • PRE-084