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

Abstract

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.

Neonatal Abstinence Syndrome

“…75 The density and affinity of m-receptors in neonates are as good as those in adults; however, evidence failed to show similar development of k-and d-receptors, as well as other receptors, in the neonatal brain. 76 A lack of opioids in a chronically stimulated state increases activity in the opioid receptors, leading to increased adenyl cyclase activity, and cellular ionic imbalance. Ultimately, this results in the increased production of various neurotransmitters through a cascade of enzymatic activities (Fig 2).…”

“…88 Various factors explain the decreased incidence in preterm neonates, including decreased cumulative exposure, 88 decreased transmission across the placenta during early gestation, 71 decreased morphine clearance, 89 decreased excretion because of immaturity of the kidneys and liver, decreased fatty tissues in preterm infants (methadone is accumulated in fatty tissue), decreased receptor development, and decreased receptor sensitivity. 76,90 Withdrawal symptoms among neonates whose mothers took an SSRI or SNRI may result from excess serotonin and noradrenaline. Neonatal withdrawal from TCA is a cholinergic rebound phenomenon.…”

Effects of Pre- and Neonatal Nicotine Exposure in Rodents: Inconsistent Evidence

“…Although rats and mice are altricial species, they are born at an earlier stage of brain development than humans (see Figure 1 in Barr et al 2011). Prenatal exposure to nicotine during the 21-to 22½-day gestational period in the rat models tobacco exposure during the fi rst 2 trimesters of human gestation, not the full-term infant.…”

“…The fi rst 6 to 12 postnatal days of life in the rat are approximately comparable to the third trimester of human gestation (Barr et al 2011;Dobbing 1971;Quinn 2005). This developmental period is characterized by rapid brain growth that includes dendritic arborization, axonal growth, peak synaptogenesis, gliogenesis, and maturation of neurotransmission.…”

IACUC Perspective on Drug Addiction Research

“…Moreover, many types of studies involve numerous ethical considerations that deter the use of human subjects. Such considerations include concerns about promoting drug taking in naïve individuals or relapse in those with drug dependence histories, exposing people to drugs with known health risks, and determining the effect of drug addiction on a developing fetus (e.g., Barr et al 2011). …”