Sigma-1 Receptor Antagonists: A New Class of Neuromodulatory Analgesics

Abstract

The sigma-1 receptor is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system. Sigma-1 receptors interact with a variety of protein targets to modify their function. These targets include several G-protein-coupled receptors such as the μ-opioid receptor, and ion channels such as the N-methyl-D-aspartate receptor (NMDAR). Sigma-1 antagonists modify the chaperoning activity of sigma-1 receptor by increasing opioid signaling and decreasing NMDAR responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions. However, the participation in pain relief of other protein partners of sigma-1 receptors in addition to opioid receptors and NMDARs cannot be ruled out. The enhanced opioid antinociception by sigma-1 antagonism is not accompanied by an increase in opioid side effects , including tolerance, dependence or constipation, so the use of sigma-1 antagonists may increase the therapeutic index of opioids. Furthermore, sigma-1 antagonists (in the absence of opioids) have been shown to exert antinociceptive effects in preclinical models of neuropathic pain induced by nerve trauma or chemical injury (the antineoplastic paclitaxel), and more recently in inflammatory and ischemic pain. Although most studies attributed the analgesic properties of sigma-1 antagonists to their central actions, it is now known that peripheral sigma-1 receptors also participate in their effects. Overwhelming preclinical evidence of the role of sigma-1 receptors in pain has led to the development of the first selective sigma-1 antagonist with an intended indication for pain treatment, which is currently in Phase II clinical trials.

Modulation by Sigma-1 Receptor of Morphine Analgesia and Tolerance: Nociceptive Pain, Tactile Allodynia and Grip Strength Deficits During Joint Inflammation

“…In this study we show that the systemic administration of S1RA was able to enhance morphine antinociception to contact heat stimulation, in agreement with previous reports which used other types of nociceptive heat stimulus (reviewed in Sánchez-Fernández et al, 2017). We show that S1RA markedly potentiated the antiallodynic effect of morphine in mice with inflammation.…”

“…Sigma-1 receptors are a promising novel pharmacological target for pain treatment (Romero et al, 2016; Sánchez-Fernández et al, 2017). Among the selective sigma-1 antagonists, the best characterized is S1RA, also known as MR309 (Vela et al, 2015).…”

“…S1RA has already been evaluated with positive results in several Phase II clinical trials for neuropathic pain (Bruna et al, 2018). Preclinical studies have shown that sigma-1 inhibition enhances the antinociception induced by opioid drugs, including morphine (reviewed in Zamanillo et al, 2013; Sánchez-Fernández et al, 2017). In addition, sigma-1 antagonism is able to rescue morphine antinociception in mice rendered tolerant to this opioid (Vidal-Torres et al, 2013; Rodríguez-Muñoz et al, 2015).…”

“…In addition, sigma-1 antagonism is able to rescue morphine antinociception in mice rendered tolerant to this opioid (Vidal-Torres et al, 2013; Rodríguez-Muñoz et al, 2015). Therefore, sigma-1 antagonists are promising tools as opioid adjuvants (Vela et al, 2015; Sánchez-Fernández et al, 2017), and in fact a further potential indication for S1RA in human patients might be to enhance opioid analgesia (Vela et al, 2015). Preclinical findings on the enhancement of opioid antinociception by sigma-1 inhibition have thus far been reported exclusively in models of nociceptive pain.…”

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).…”