Neonatal Animal Models of Opiate Withdrawal

Abstract

The symptoms of opiate withdrawal in infants are defined as neonatal abstinence syndrome (NAS). NAS is a significant cause of morbidity in term and preterm infants. Factors, such as polysubstance abuse, inadequate prenatal care, nutritional deprivation, and the biology of the developing central nervous system contribute to the challenge of evaluating and treating opiate-induced alterations in the newborn. Although research on the effects of opiates in neonatal animal models is limited, the data from adult animal models have greatly contributed to understanding and treating opiate tolerance, addiction, and withdrawal in adult humans. Yet the limited neonatal data that are available indicate that the mechanisms involved in these processes in the newborn differ from those in adult animals, and that neonatal models of opiate withdrawal are needed to understand and develop effective treatment regimens for NAS. In this review, the behavioral and neurochemical evidence from the literature is presented and suggests that mechanisms responsible for opiate tolerance, dependence, and withdrawal differ between adult and neonatal models. Also reviewed are studies that have used neonatal rodent models, the authors' preliminary data based on the use of neonatal rat and mouse models of opiate withdrawal, and other neonatal models that have been proposed for the study of neonatal opiate withdrawal.

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

“…Withdrawal behaviors resulting from fetal exposure are difficult to score in mice at birth (Richardson et al, 2006), likely owing, at least partially, to developmental delay in mice compared with humans (Workman et al, 2013). Nevertheless, the postnatal mouse model is relatively accessible with robust behavioral outcomes, and bears the one key feature that makes it relevant to NAS: lack of a mature BBB, which is an important novel finding of this study.…”

“…Previous studies have been mixed in demonstrating robust withdrawal behaviors at birth in rodents, ranging from weak effects in rats (Enters et al, 1991;Robinson and Wallace, 2001) to no effects in mice (Richardson et al, 2006). Using the same opiate delivery paradigm in pregnant rats, more robust withdrawal behaviors are detectable 7 days after birth (Barr et al, 1998), and similarly, if morphine is delivered by direct injection in rat pups anytime after P7, robust preweaning withdrawal behaviors can be induced by naloxone (Jones and Barr, 1995).…”

A Novel Strategy for Attenuating Opioid Withdrawal in Neonates

“…Further, this approach also appears to selectively diminish alterations in brain glucose metabolism in regions associated with fear inhibition, vision, and attention shifts that persist into adolescence. With respect to the clinical implications of these findings, it should be noted that in rats, it is generally accepted that the first two human trimester equivalents occur in utero, between GD 1-21, while the third human trimester equivalent occurs ex utero, from PND 1-7 [30,37]. Thus, in the present study, prenatal GVG treatment occurred during the human equivalent of the terminus of the second trimester.…”

“…For these reasons, we employed a more consistent approach in the service of establishing a preclinical animal model that may be used in the subsequent development of new treatment strategies for NAS. Specifically, using an acute dose of the full agonist, naloxone, withdrawal behaviours occur in a quicker, more intense, and most importantly, more reproducible manner [30,42–44]. That is, this acute precipitated design was chosen to ensure that opioid withdrawal behaviour could be recorded and scored within a timeframe that is considerably shorter and far more consistent.…”

“…Naloxone administration rapidly induced withdrawal. Videos were time sampled at 15 min intervals and were scored for frequency of locomotion, rolling, curling, and stretching [29,30], by three trained raters blinded to the treatment condition.…”