Human opiorphin: The lack of physiological dependence, tolerance to antinociceptive effects and abuse liability in laboratory mice

Like other endogenous enkephalinase inhibitors, human opiorphin peptide (QRFSR) attenuates catabolism of enkephalins and appears to be a promising therapeutic, displaying antinociceptive action in several pain models. However, its opioid-like side-effect profile is insufficiently characterized. In the present set of experiments, acute intraperitoneal administration of opiorphin produced an antinociceptive effect in the tail-flick test in mice (0.3 mg/kg) and this action was inhibited by opioid receptor antagonist naloxone (3 mg/kg). Repeated treatment with opiorphin changed the antinociceptive response neither to itself nor to morphine, suggesting the lack of tolerance and morphine cross-tolerance, respectively. Repeated treatment with opiorphin (3 mg/kg) also failed to produce opioid dependence. Opiorphin (0.3 or 1 mg/kg) produced no rewarding effects in the conditioned place preference test. However, at the dose of 3 mg/kg, the peptide produced antidepressant-like effect in the forced swim test, and it did not affect locomotor activity. The present set of results confirms the beneficial effects of opiorphin in pain management, and suggests a lack of opioid-like side effects as well as the presence of antidepressant-like actions of this peptide.