Abstract
Sigma-1 receptor (σ1R) antagonism increases the effects of morphine on acute nociceptive pain. S1RA (E-52862) is a selective σ1R antagonist widely used to study the role of σ1Rs. S1RA alone exerted antinociceptive effect in the formalin test in rats and increased noradrenaline levels in the spinal cord, thus accounting for its antinociceptive effect. Conversely, while systemic S1RA failed to elicit antinociceptive effect by itself in the tail-flick test in mice, it did potentiate the antinociceptive effect of opioids in this acute pain model. The present study aimed to investigate the site of action and the involvement of spinal noradrenaline on the potentiation of opioid antinociception by S1RA on acute thermal nociception using the tail-flick test in rats. Local administration was performed after intrathecal catheterization or intracerebroventricular and rostroventral medullar (RVM) cannulae implantation. Noradrenaline levels in the spinal cord were evaluated using the concentric microdialysis technique in awake, freely-moving rats. Systemic or supraspinal administration of S1RA alone, while having no effect on antinociception, enhanced the effect of morphine in rats. However, spinal S1RA administration did not potentiate the antinociceptive effect of morphine. Additionally, the peripherally restricted opioid agonist loperamide was devoid of antinociceptive effect but produced antinociception when combined with S1RA. Neurochemical studies revealed that noradrenaline levels in the dorsal horn of the spinal cord were not increased at doses exerting potentiation of the antinociceptive effect of the opioid. In conclusion, the site of action of σ1R for opioid modulation on acute thermal nociception is located at the peripheral and supraspinal levels, and the opioid-potentiating effect is independent of the spinal noradrenaline increase produced by S1RA.
Highlights
The sigma-1 receptor (σ1R) 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
We previously reported that co-administration of S1RA with several opioids used in clinics results in an enhancement of the antinociception but not of undesired opioid-induced phenomena such as the development of analgesic tolerance, physical dependence, or inhibition of gastrointestinal transit
We previously reported that S1RA (80 mg/kg) increased NA levels in the dorsal horn of the spinal cord and that this effect correlated well with the antinociceptive effect of S1RA in the formalin-induced pain model (Vidal-Torres et al, 2014)
Summary
The sigma-1 receptor (σ1R) 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. S1RA ( known as MR309 or E-52862) is a σ1R antagonist with high affinity for σ1R, good σ1/σ2 selectivity ratio (>550), and selectivity against a panel of 170 receptors, enzymes, transporters, and ion channels (Romero et al, 2012). We previously reported that co-administration of S1RA with several opioids used in clinics results in an enhancement of the antinociception but not of undesired opioid-induced phenomena such as the development of analgesic tolerance, physical dependence, or inhibition of gastrointestinal transit. It has shown good safety and tolerability profiles after single and multiple doses in healthy humans in phase I clinical trials (Abadias et al, 2013); S1RA has shown promising results in phase II clinical trial for neuropathic pain (Bruna et al, 2018)
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