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.
Highlights
Inflammatory pain is characterized by a decrease in the cutaneous sensory threshold, and by pain-induced decreases in physical function, which affect the quality of life of patients with inflammatory conditions (Salaffi et al, 2009)
We compared the effects of morphine, S1RA and their association on three different pain measures: nociceptive heat pain, inflammatory tactile allodynia, and grip strength deficits induced by inflammation
Our findings show that morphine was able to induce analgesiclike effects on nociceptive heat pain, inflammatory tactile allodynia and grip strength deficits induced by inflammation
Summary
Inflammatory pain is characterized by a decrease in the cutaneous sensory threshold, and by pain-induced decreases in physical function, which affect the quality of life of patients with inflammatory conditions (Salaffi et al, 2009). Alterations in von Frey thresholds and pain-induced grip strength deficits during inflammation result (at least partially) from non-overlapping mechanisms, including the involvement of different subsets of primary afferents (Montilla-García et al, 2017). Despite their differences, both of these outcomes are sensitive to opioid analgesics, which can restore both normal sensory thresholds and physical functioning (Montilla-García et al, 2017). 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). It is known that opioid receptor functioning can change during inflammation (reviewed in Stein et al, 2009); the mechanisms involved in the modulation of opioid antinociception by sigma-1 receptor may not be the same during inflammation as in conditions not involving injury
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