Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms

Inmaculada Bravo-Caparrós; Gloria Perazzoli; Sandra Yeste; Domagoj Cikes; José Manuel Baeyens; Enrique José Cobos; Francisco Rafael Nieto

doi:10.3389/fphar.2019.00613

Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms

Front Pharmacol. 2019 Jun 12:10:613. doi: 10.3389/fphar.2019.00613. eCollection 2019.

Authors

Inmaculada Bravo-Caparrós^{1

2

3}, Gloria Perazzoli^{3

4}, Sandra Yeste⁵, Domagoj Cikes⁶, José Manuel Baeyens^{1

2

3}, Enrique José Cobos^{1

2

3

7}, Francisco Rafael Nieto^{1

2

3}

Affiliations

¹ Department of Pharmacology, School of Medicine, University of Granada, Granada, Spain.
² Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain.
³ Biosanitary Research Institute, University Hospital Complex of Granada, Granada, Spain.
⁴ Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada, Spain.
⁵ Drug Discovery and Preclinical Development, Esteve, Barcelona, Spain.
⁶ Institute of Molecular Biotechnology, Vienna, Austria.
⁷ Teófilo Hernando Institute for Drug Discovery, Madrid, Spain.

Abstract

Sigma-1 (σ₁) receptor antagonists are promising tools for neuropathic pain treatment, but it is unknown whether σ₁ receptor inhibition ameliorates the neuropathic signs induced by nerve transection, in which the pathophysiological mechanisms and response to drug treatment differ from other neuropathic pain models. In addition, σ₁ antagonism ameliorates inflammatory pain through modulation of the endogenous opioid system, but it is unknown whether this occurs during neuropathic pain. We investigated the effect of σ₁ inhibition on the painful hypersensitivity associated with the spared nerve injury (SNI) model in mice. Wild-type (WT) mice developed prominent cold (acetone test), mechanical (von Frey test), and heat hypersensitivity (Hargreaves test) after SNI. σ₁ receptor knockout (ခσ₁-KO) mice did not develop cold allodynia and showed significantly less mechanical allodynia, although they developed heat hyperalgesia after SNI. The systemic acute administration of the selective σ₁ receptor antagonist S1RA attenuated all three types of SNI-induced hypersensitivity in WT mice. These ameliorative effects of S1RA were reversed by the administration of the σ₁ agonist PRE-084, and were absent in σ₁-KO mice, indicating the selectivity of S1RA-induced effects. The opioid antagonist naloxone and its peripherally restricted analog naloxone methiodide prevented S1RA-induced effects in mechanical and heat hypersensitivity, but not in cold allodynia, indicating that opioid-dependent and -independent mechanisms are involved in the effects of this σ₁ antagonist. The repeated administration of S1RA twice a day during 10 days reduced SNI-induced cold, mechanical, and heat hypersensitivity without inducing analgesic tolerance during treatment. These effects were observed up to 12 h after the last administration, when S1RA was undetectable in plasma or brain, indicating long-lasting pharmacodynamic effects. These data suggest that σ₁ antagonism may have therapeutic value for the treatment of neuropathic pain induced by the transection of peripheral nerves.

Keywords: S1RA; cold allodynia; endogenous opioid system; heat hyperalgesia; mechanical allodynia; neuropathic pain; sigma-1 receptors; spared nerve injury.