The Sigma 2 receptor promotes and the Sigma 1 receptor inhibits mu-opioid receptor-mediated antinociception

Pilar Sánchez-Blázquez,Elsa Cortés-Montero,Manuel Merlos,María Rodríguez-Muñoz,Javier Garzón-Niño

doi:10.1186/s13041-020-00676-4

Abstract

The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R−/− mice and diminished in σ2R−/− mice. The analgesic effect of morphine was increased in σ2R−/− mice by treatment with S1RA. However, σ2R−/− mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neuropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.

Highlights

Sigma receptors are unique transmembrane proteins expressed throughout the central nervous system and in certain peripheral tissues
Targeted deletion of the Sigma-2 receptor (σ2R) gene was not accompanied by compensatory changes in the levels of mRNAs encoding critical proteins in our study, such as Sigma-1 receptor (σ1R), mu-opioid receptors (MOR) or MOR- and σ1R-regulated histidine triad nucleotide-binding protein
Several studies have demonstrated that σ1R−/− mice do not develop allodynia in different animal models of neuropathic pain such as constriction injury (CCI) [33], paclitaxel [34], spinal cord contusion injury [35], or spare nerve injury [36]

Summary

Introduction

Sigma receptors (σRs) are unique transmembrane proteins expressed throughout the central nervous system and in certain peripheral tissues. The σ1R was initially identified in 1976 as a member of the plasma membrane opioid receptor family [5], while σ2R was not discovered until later. ΣRs were described to bind to radioligands in preparations of brain synaptosomes. The σ1R was purified, sequenced and cloned from guinea pig brain in 1996, and it bears little sequence homology to any known mammalian receptor [9]. Σ2R is involved in several disease states, and the utility of its Sánchez‐Blázquez et al Mol Brain (2020) 13:150 exogenous ligands as cancer therapeutics and diagnostic tools has been reported [15,16,17]. Similar to the ligands of σ1R, certain molecules that bind to σ2R reduce mechanical hypersensitivity in a spared nerve injury model [20]

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Conclusion