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.