Melatonin as a potential counter-effect of hyperalgesia induced by neonatal morphine exposure

•Melatonin reduce hyperalgesia induced by neonatal morphine exposure.•Neonatal morphine exposure promotes long-term changes on nociceptive pathways.•Repeated low-dose of neonatal morphine induces hyperalgesia in adult rats.•Melatonin exerts its antinociceptive action by β-endorphin release in the SNC. Morphine administration in the neonatal period can induce long-term effects in pain circuitry leading to hyperalgesia induced by the opioid in adult life. This study explored a new pharmacological approach for reversing this effect of morphine. We focused on melatonin owing its well-known antinociceptive and anti-inflammatory effects, and its ability to interact with the opioid system. We used the formalin test to assess the medium and long-term effects of melatonin administration on hyperalgesia induced by morphine in early life. Newborn rats were divided into two groups: the control group, which received saline, and the morphine group, which received morphine (5μg subcutaneously [s.c.]) in the mid-scapular area, once daily for 7days, from P8 (postnatal day 8) until P14. At postnatal days 30 (P30) and 60 (P60), both groups were divided in two subgroups, which received melatonin or melatonin vehicle 30min before the formalin test. The nociceptive responses were assessed by analyzing the total time spent biting, flicking, and licking the formalin-injected hind paw; these responses were recorded during the first 5min (neurogenic/acute phase) and from 15 to 30min (inflammatory/tonic phase). Initially, animals in the morphine/vehicle group showed increased nociceptive behavior in phase II (inflammatory) of the formalin test at P30, and in the neurogenic and inflammatory phases at P60. These increased nociceptive responses were fully reversed by melatonin administration at either age. These findings show that melatonin administration is a potential means for countering hyperalgesia induced by neonatal morphine exposure in young and adult rats.