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

Abstract

Sigma-1 receptor antagonism increases the effects of morphine on nociceptive pain, even in morphine-tolerant animals. However, it is unknown whether these receptors are able to modulate morphine antinociception and tolerance during inflammatory pain. Here we used a mouse model to test the modulation of morphine effects by the selective sigma-1 antagonist S1RA (MR309), by determining its effect on inflammatory tactile allodynia (von Frey filaments) and on grip strength deficits induced by joint inflammation (a measure of pain-induced functional disability), and compared the results with those for nociceptive heat pain recorded with the unilateral hot plate (55°C) test. The subcutaneous (s.c.) administration of morphine induced antinociceptive effects to heat stimuli, and restored mechanical threshold and grip strength in mice with periarticular inflammation induced by Complete Freund’s Adjuvant. S1RA (80 mg/kg, s.c.) administered alone did not induce any effect on nociceptive heat pain or inflammatory allodynia, but was able to partially reverse grip strength deficits. The association of S1RA with morphine, at doses inducing little or no analgesic-like effects when administered alone, resulted in a marked antinociceptive effect to heat stimuli and complete reversion of inflammatory tactile allodynia. However, S1RA administration did not increase the effect of morphine on grip strength deficits induced by joint inflammation. When S1RA (80 mg/kg, s.c.) was administered to morphine-tolerant animals, it rescued the analgesic-like effects of this opioid in all three pain measures. However, when S1RA was repeatedly given during the induction of morphine tolerance (and not on the day of behavioral evaluation) it failed to affect tolerance to the effects of morphine on nociceptive heat pain or inflammatory allodynia, but completely preserved the effects of this opioid on grip strength deficits. These effects of S1RA on morphine tolerance cannot be explained by pharmacokinetic interactions, given that the administration of S1RA did not modify concentrations of morphine or morphine-3-glucuronide (a major morphine metabolite) in morphine-tolerant animals in plasma or brain tissue. We conclude that sigma-1 receptors play a pivotal role in the control of morphine analgesia and tolerance in nociceptive and inflammatory pain, although in a manner dependent on the type of painful stimulus explored.

Sigma‐1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain

“…Earlier preclinical research had shown this modulatory role in the absence of chronic pain, using σ1 receptor knockout mice and σ1 receptor antagonists (Chien & Pasternak, ; Sánchez‐Fernández et al, ; Sánchez‐Fernández et al, ). Moreover, E‐52862 demonstrated efficacy restoring morphine analgesia in tolerant animals with acute nociceptive and inflammatory pain (Montilla‐García et al, ; Rodríguez‐Muñoz, Sánchez‐Blázquez, et al, ; Vidal‐Torres et al, ). Surprisingly, there were no previous studies assessing the role of σ1 receptors in modulation of opioid analgesia under conditions of chronic pain.…”

“…Moreover, functional interactions have been reported between σ1 receptors and μ‐opioid receptors (Kim et al, ). Indeed, σ1 receptor antagonists enhance opioid‐induced analgesia in rodent models of acute nociception and inflammation (Chien & Pasternak, ; Montilla‐García et al, ; Vidal‐Torres et al, ) and did not potentiate opioid‐induced side effects such as tolerance or physical dependence (Vidal‐Torres et al, ), which could represent an important advantage for long‐term opioid treatment. However, it is not known if σ1 receptors modulate opioid analgesia and tolerance during osteoarthritis chronic pain.…”

Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms

“…The sigma-1 receptor was also a promising therapeutic target for the treatment of alcohol addiction [ 143 ], methamphetamine addiction [ 144 , 145 , 146 ], and cocaine addiction [ 147 , 148 , 152 ]. The sigma-1 receptor antagonist showed analgesic effects to relieve the symptoms in several peripheral neuropathy models [ 153 , 154 , 155 , 156 ]. MR309, a selective and novel antagonist of the sigma-1 receptor [ 164 ], has been tested in a phase II clinical trial, suggesting the promising action for oxaliplatin-induced peripheral neuropathic pain relief in patients [ 165 ]].…”

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

“…threshold force in mice when von Frey filaments are used is typically about 1 g (e.g. Montilla-García et al, 2019;Cobos et al, 2018), whereas an electronic device with a rigid filament yields a threshold of about 5-6 g (e.g. Nieto et al, 2012 and2014).…”

“…This technique was recently adapted to study pain resulting from a variety of etiologies mostly affecting the limbs, such as muscle inflammation (Kehl et al, 2000 andSouza et al, 2018), muscle pain induced by repeated exercise (Fujiwara et al, 2017), musculoskeletal hyperalgesia induced by stress (Goudie-DeAngelis et al, 2016), bone cancer (Kehl and Fairbanks, 2003;Wacnik et al, 2003), osteoarthritis (e.g. Chandran et al, 2009;Honore et al, 2009;Lee et al, 2011;Hinata et al, 2018), inflammatory joint pain (Montilla-García et al, 2017;Dutta et al, 2018;Montilla-García et al, 2019), osteoporosis (Suzuki et al, 2018), and a model of sickle cell disease (Calhoun et al, 2015), among others. Grip strength deficits have also been observed during discogenic back pain (Millecamps et al, 2015;Millecamps and Stone, 2018;Yang et al, 2018), indicating that this outcome may be useful to detect pain even if the injury is not located in the limbs.…”