Changing Mechanisms of Opiate Tolerance and Withdrawal during Early Development: Animal Models of the Human Experience

Human infants may be exposed to opiates through placental transfer from an opiate-using mother or through the direct administration of such drugs to relieve pain (e.g., due to illness or neonatal surgery). Infants of many species show physical dependence and tolerance to opiates. The magnitude of tolerance and the nature of withdrawal differ from those of the adult. Moreover, the mechanisms that contribute to the chronic effects of opiates are not well understood in the infant but include biological processes that are both common to and distinct from those of the adult. We review the animal research literature on the effects of chronic and acute opiate exposure in infants and identify mechanisms of withdrawal and tolerance that are similar to and different from those understood in adults. These mechanisms include opioid pharmacology, underlying neural substrates, and the involvement of other neurotransmitter systems. It appears that brain circuitry and opioid receptor types are similar but that NMDA receptor function is immature in the infant. Intracellular signaling cascades may differ but data are complicated by differences between the effects of chronic versus acute morphine treatment. Given the limited treatment options for the dependent infant patient, further study of the biological functions that are altered by chronic opiate treatment is necessary to guide evidenced-based treatment modalities.