Morphine exposure in early life increases nociceptive behavior in a rat formalin tonic pain model in adult life

Considering the importance of a deeper understanding of the effect throughout life of opioid analgesia at birth, our objective was to determine whether morphine administration in early life, once a day for 7 days in 8-day-old rats, alters the nociceptive response over the short (P16), medium (P30), and long term (P60) and to evaluate which system is involved in the altered nociceptive response. The nociceptive responses were assessed by the formalin test, and the behavior analyzed was the total time spent in biting and flicking of the formalin-injected hindpaw, recorded during the first 5 min (phase I) and from 15-30 min (phase II). The morphine group showed no change in nociceptive response at P16, but at P30 and P60, the nociceptive response was increased in phase I, and in both phases, respectively. At P30 and P60, the animals received a non-steroidal anti-inflammatory drug (indomethacin) or NMDA receptor antagonist (ketamine) 30 min before the formalin test. The increase in the nociceptive response was completely reversed by ketamine, and partially by indomethacin. These results indicate that early morphine exposure causes an increase in the nociceptive response in adult life. It is possible that this lower nociception threshold is due to neuroadaptations in nociceptive circuits, such as the glutamatergic system. Thus, this work demonstrates the importance of evaluating clinical consequences related to early opioid administration and suggests a need for a novel design of agents that may counteract opiate-induced neuroplastic changes.