Sigma-1 receptor antagonism as a promising strategy for postoperative pain treatment: A study in laparotomized mice

Postoperative pain remains a major clinical challenge, as it often persists despite analgesic treatment even with opioids. We studied the effects of sigma-1 receptor antagonists (BD-1063 and S1RA), administered alone or in combination with the µ-opioid morphine, on three key aspects of postoperative pain in mice with a transverse laparotomy: tactile allodynia, pain at rest, and movement-induced pain. Sigma-1 antagonism and morphine induced antiallodynic effects sensitive to peripheral opioid antagonism by naloxone methiodide, although only sigma-1 antagonism was sensitive to the sigma-1 agonist PRE-084. The antiallodynic effect of sigma-1 antagonism was also reversed by the μ-opioid antagonist cyprodime and by depletion of neutrophils, which express high levels of proopiomelanocortin, the precursor of the µ-opioid agonist ß-endorphin. Morphine, but not sigma-1 antagonism, reversed pain at rest, and none of the drugs tested improved movement-induced pain. Notably, the combination of S1RA and morphine at doses ineffective when administered alone, fully reversed tactile allodynia, pain at rest, and movement-induced pain, and in a manner sensitive to PRE-084 and naloxone methiodide, indicating the simultaneous participation of both sigma-1 and peripheral opioid receptors. Therefore, sigma-1 antagonism boosts the actions of endogenous opioid peptides from neutrophils only to reverse tactile allodynia, but when combined with morphine, it enhances peripheral opioid analgesia to reverse all aspects of postoperative pain. Finally, S1RA did not enhance morphine-induced inhibition of gastrointestinal transit or rewarding effects. Modulation of opioid analgesia by sigma-1 receptors might have potential clinical application to increase the therapeutic range of opioids in the treatment of postoperative pain.