Sigma-1 Receptor and Pain

Abstract

There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy respect to existing therapies and/or reduce their unwanted effects. Current preclinical evidence supports the modulatory role of the sigma-1 receptor (σR) in nociception, mainly based on the pain-attenuated phenotype of σR knockout mice and on the antinociceptive effect exerted by σR antagonists on pain of different etiology, very consistently in neuropathic pain, but also in nociceptive, inflammatory, and visceral pain. σR is highly expressed in different pain areas of the CNS and the periphery, particularly dorsal root ganglia (DRG), and interacts and modulates the functionality of different receptors and ion channels. Accordingly, antinociceptive effects of σR antagonists both acting alone and in combination with other analgesics have been reported at both central and peripheral sites. At the central level, behavioral, electrophysiological, neurochemical, and molecular findings support a role for σR antagonists in inhibiting augmented excitability secondary to sustained afferent input. Moreover, the involvement of σR in mechanisms regulating pain at the periphery has been recently confirmed. Unlike opioids, σR antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitivity effects (antihyperalgesic and antiallodynic) in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. These are distinctive features allowing σR antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain.

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice

“…In this regard, several preclinical studies have shown that sigma-1 receptor (σ1R) may play a critical role in the development of pathological pain (Merlos et al., 2017). Interestingly, the genetic ablation of σ1R in peripheral injury-induced pathological pain models resulted in either attenuation or avoidance of pain-related behaviors in mice (Cendán et al., 2005; de la Puente et al., 2009; Entrena et al., 2009a; Nieto et al., 2012; Tejada et al., 2014; Gris et al., 2015).…”

Sigma‐1 Receptor Expression in DRG Neurons During a Carrageenan‐Provoked Inflammation

“…Beside its direct effects in causing pain hypersensitivity, it was also found that σ1R tonically modulates opioid analgesia. Both of these effects offer the potential for pharmaceutical modulation of σ1R in treatment of pain (Romero et al, ; Merlos et al, ). Specifically, its peripheral effects are the most interesting, as the strongest expression of σ1R in the nervous system was observed in primary afferent DRG neurons (Bangaru et al, ; Mavlyutov et al, ).…”

“…Specifically, its peripheral effects are the most interesting, as the strongest expression of σ1R in the nervous system was observed in primary afferent DRG neurons (Bangaru et al, ; Mavlyutov et al, ). In DRG neurons, it causes modulation of the activity of receptors for neurotransmitters and different types of ion channels, thus modulating the perception of pain (Merlos et al, ).…”

“…Since σ1R are not activated in physiological, only under pathological conditions (Merlos et al, ), they emerge as a promising target for pharmacological manipulation in the treatment of pain. Two aspects appeared particularly interesting: their direct effects in causing pain hypersensitivity, as well as their modulation of opioid analgesia (Romero et al, ; Merlos et al, ). Specifically, their peripheral effects are potentially therapeutically interesting, since their strongest expression in the nervous system was observed in primary afferent dorsal root ganglion (DRG) neurons (Bangaru et al, ; Mavlyutov et al, ).…”

Supraspinal and Peripheral, but Not Intrathecal, σ1R Blockade by S1RA Enhances Morphine Antinociception

“…The sigma-1 receptor (σ 1 R) has been described as the first ligand-regulated molecular chaperone located at the endoplasmic reticulum and plasma membranes whose activity is regulated in an agonist-antagonist manner. The σ 1 R is expressed in key areas for pain control and there is cumulative evidence supporting an involvement of the σ 1 R mainly in two kinds of pain conditions: (1) those involving sensitization, e.g., after sensitization with capsaicin or formalin or following nerve injury where σ 1 R antagonists by themselves inhibit pain behaviors in the absence of opioids (Romero et al, 2012; Vidal-Torres et al, 2014; Gris et al, 2016); and (2) in acute pain conditions after the application of mechanical (paw pressure test) or thermal (tail-flick and hot plate tests) nociceptive stimuli, where σ 1 R antagonists by themselves fail to modify the nociceptive thresholds but enhance opioid-induced antinociception (Sánchez-Fernández et al, 2013; Vidal-Torres et al, 2013; Merlos et al, 2017; Sánchez-Fernández et al, 2017).…”