Role of κ- and δ-opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice

Abstract Oxytocin has been implicated in the modulation of somatosensory transmission such as nociception and pain. The present study investigates the effect of oxytocin on formalin-induced pain response, a model of tonic continuous pain. The animals were injected with 0.1 ml of 1% formalin in the right hindpaw and the left hindpaw was injected with an equal volume of normal saline. The time spent by the animals licking or biting the injected paw during 0–5 min (early phase) and 20–25 min (late phase) was recorded separately. Oxytocin (25, 50, 100 μg/kg, i.p.) dose dependently decreased the licking/biting response, both in the early as well as the late phases. The antinociceptive effect of oxytocin (100 μg/kg, i.p.) was significantly attenuated in both the phases by a higher dose of the non-selective opioid receptor antagonist naloxone (5 mg/kg, i.p.), MR 2266 (0.1 mg/kg, i.p.), a selective κ-opioid receptor antagonist and naltrindole (0.5 mg/kg, i.p.), a selective δ-opioid receptor antagonist but not by a lower dose of naloxone (1 mg/kg, i.p.) or β-funaltrexamine (2.5 μg/mouse, i.c.v.), a selective μ-opioid receptor antagonist. Nimodipine, a calcium channel blocker (1 and 5 mg/kg, i.p.) produced a dose-dependent analgesic effect. The antinociceptive effect of oxytocin was significantly enhanced by the lower dose of nimodipine (1 mg/kg, i.p.) in both the phases. Chronic treatment with oxytocin (100 μg/kg/day, i.p. daily for 7 days) did not produce tolerance in both the phases of formalin-induced pain response. The results thus indicate that oxytocin displays an important analgesic response in formalin test; both κ- and δ-opioid receptors as well as voltage-gated calcium channels seem to be involved in the oxytocin-induced antinociception.