Abstract
Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10–45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09–1.82) and 2.31 (1.02–4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31–7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7–25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29–15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85–5.18) mg/kg, i.p.] in the 55°C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.
Highlights
Chronic pain is the number one cause of adult disability in the United States
We first completed the characterization of a set of established control analgesics in the mouse constriction injury (CCI) assay of neuropathic pain
Following administration through the intraperitoneal (i.p.) route and using von Frey filaments to measure mechanical allodynia, the mu-opioid receptor agonist, morphine (10 mg/kg), the sigmareceptor antagonist E52862 (30 mg/kg), and the established treatment for neuropathic pain, gabapentin (50 mg/kg, given 60 min prior to testing), all significantly attenuated the reduced paw withdrawal threshold caused by CCI (factor treatment: F(3,151) = 4.01, p = 0.009 and factor time: F(3,151) = 31.7, p < 0.0001; two-way ANOVA and Tukey’s multiple comparison post hoc test; Figure 2)
Summary
Chronic pain is the number one cause of adult disability in the United States. Sigma Antagonists Reduce Neuropathic Pain antidepressants (e.g., amitriptyline, desipramine) and mu opioid receptor (MOR)-selective agonists (e.g., morphine), but the liabilities of these treatments greatly offset their therapeutic benefits (Yaksh and Wallace, 2011). These agents all cause drowsiness and impair locomotor ability, posing a significant risk when operating machinery and increasing the risk of falling, which in the elderly has been linked to increased mortality risk (Calandre et al, 2016; Mangram et al, 2016). There remains a clear need for new, safer non-opioid options to treat chronic pain
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