A Method for Chronic Drug Delivery in Neonates
Teratology studies aimed at investigating neonatal learning, memory, behavior or development present unique challenges to scientists because they require manipulation of young, very small animals during a critical developmental period. Authors of numerous rodent studies have concluded that environmental manipulations occurring early in life result in physiological and behavioral changes that persist into adulthood. 1,2,3 Some studies have shown that human handling of newborn rats for as little as 15-20 minutes daily during the first few weeks of life produces neuroendocrine, neurochemical and behavioral alterations in the adult. 2,4,5 Some methods of drug administration impose severe experimental conditions, such as repetitive handling and injections, which have more dramatic implications for neonatal development. Furthermore, such experimental artifacts are likely to confound and compromise research results.
Effects on Physical and Neurobehavioral Development
ALZET Osmotic Pumps have long been used as an alternative to repeated injections for chronic administration of experimental agents in unrestrained laboratory animals. These small, implantable pumps present an attractive alternative for use in neonates as well. Doucette et al., at the University of Prince Edward Island, demonstrated the value of these miniature infusion pumps as a method for sustained drug delivery in neonatal rats. 6 These investigators used 8-day old Sprague-Dawley rat pups that were randomly assigned to one of three treatment groups: ALZET pump implantation, sham surgery, or no surgery. Saline filled ALZET pumps (Model 1003D) were aseptically implanted under the skin of rat pups under isofluorane anesthesia. The pups were allowed to recover from the anesthesia before being returned to their cages. The entire surgical procedure took an average of 10 minutes and was never longer than 20 minutes. Rats in the sham surgery control group received identical treatment except pump insertion. The rats not operated on were left undisturbed. Animals were evaluated at various times over a 72-day period using a standard battery of tests designed to measure physical and neurobehavioral development, such as weight gain, fur development, incisor eruption, startle, visual placing, and others. With the exception of transient decreases in weight gain during the first 24 to 48 hours following pump implantation, no significant differences were found in rats implanted with pumps compared to the control and sham treated rats on any of the parameters evaluated.
Doucette et al. attributed their experimental success, in part, to the careful use of good laboratory procedures to help minimize surgical stress. They emphasized the importance of following strict aseptic technique during the pump implantation in order to decrease the risk of infection. Additionally, they found the use of an inhaled anesthetic, isofluorane, which permits rapid induction and recovery, to be preferable to slower acting inhaled or injectable anesthetics. The authors concluded that the implantation of ALZET pumps, under carefully controlled surgical conditions, does not significantly affect neurobehavioral development in rat pups, thus they represent a viable alternative to repeated injections for sustained drug delivery.
Experimental Model of Neonatal Opioid Tolerance and Dependence
Many experimental models of opioid tolerance and dependence use repeated drug administration by bolus injection with a variety of dosing schedules. Such dosing schedules lead to wide fluctuations of opioid concentrations in the central nervous system that may affect the development of tolerance. Additionally, the added stress from repeated handling and injections could affect the development of tolerance as well. Investigators at the Medical College of Virginia have used ALZET pumps successfully to establish an animal model of neonatal opioid tolerance and physical dependence. Using this experimental model, Thornton et al. have characterized tolerance and dependence to fentanyl and morphine in neonatal rats. 7,8 Their studies indicate that continuous subcutaneous delivery using ALZET pumps is particularly useful since it closely mimics the intravenous route by which opioids are continuously administered to human neonates. 7 Another key benefit of the ALZET pumps in these experiments was their ability to maintain stable plasma and tissue opioid levels, thus reducing toxicity associated with widely fluctuating plasma levels typical with conventional dosing methods. Furthermore, the pumps provided a means of chronic opioid delivery that minimized neonatal handling and the stress commonly seen with repeated injections.
Since these initial studies were published in 1997, the Virginia research group has produced a number of publications describing further research on the long-term consequences of opioid tolerance and dependence established during the neonatal stage. 9.10,11,12 Thornton et al. have now incorporated ALZET pumps as their standard method for chronic opioid administration in neonatal rats. To obtain a complete list of references on the use of ALZET pumps in neonates, a package of information on surgical techniques for neonates, or additional information about ALZET Osmotic Pumps please contact ALZET technical services.
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