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

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

doi:10.3389/fphar.2019.00613

Inmaculada Bravo-Caparrós, Enrique José Cobos + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2019.00613

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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.

Highlights

Neuropathic pain is a debilitating chronic pain condition resulting from a lesion or disease of the somatosensory system (Colloca et al, 2017)
We studied the involvement of the σ1 receptor in neuropathic pain after spared nerve injury (SNI) by comparing the response to mechanical, heat, and cold stimuli in WT and σ1 receptor knockout (σ1-KO) female mice
The main findings of the present study are that: 1) pharmacological antagonism or genetic inactivation of σ1 receptors reduces neuropathic pain induced by peripheral nerve transection (SNI model); 2) the ameliorative effects on SNI-induced hypersensitivity to mechanical and heat stimuli produced by σ1 receptor antagonism are mediated by modulation of the endogenous opioid system; and 3) repeated treatment with S1RA induces prolonged ameliorative effects which lasted longer than the presence of the drug in the organism

Summary

Introduction

Neuropathic pain is a debilitating chronic pain condition resulting from a lesion or disease of the somatosensory system (Colloca et al, 2017). The sigma-1 (σ1) receptor is a unique ligand-operated chaperone expressed at high levels in several key pain control areas in both the peripheral and central nervous system, where it interacts with different receptors and ion channels to modulate them (Su et al, 2016; Sánchez-Fernández et al, 2017). Substantial evidence points to a prominent role for these receptors in neuropathic pain of diverse etiology (Merlos et al, 2017; Sánchez-Fernández et al, 2017), and shows that pain-like behaviors are attenuated in σ1-knockout (KO) mice (de la Puente et al, 2009; Nieto et al, 2012) and in wild-type (WT) animals treated with σ1 receptor antagonists (Roh et al, 2008; Nieto et al, 2012; Romero et al, 2012; Gris et al, 2016; Kang et al, 2016). The mechanisms involved in the antineuropathic effects of σ1 inhibition are only partially known and have been well studied in the central nervous system, in the dorsal spinal cord, where these receptors control central sensitization (reviewed in Sánchez-Fernández et al, 2017)

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