DEVELOPMENTAL NEUROCHEMISTRY OF BUPRENORPHINE

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Methadone is used in the management of the pregnant opioid addict. However, methadone maintenance has been associated with neonatal withdrawal as well as with behavioral and neurochemical anomalies in both human and animals. Buprenorphine may be a useful drug in the pregnant addict, as it is not associated with an abstinence syndrome. Furthermore, buprenorphine may be superior to methadone during pregnancy, as it lacks full agonist activity at mu-opioid receptors, and thus may not produce the neurochemical changes observed after prenatal methadone exposure. However, unlike methadone, buprenorphine binds to delta- and kappa-opioid receptors, which may result in a different set of neural and behavioral perturbations in the offspring. This project will study the effects of buprenorphine on the developing organism. Rats will be exposed to various doses of buprenorphine pre- and/or postnatally via maternally-implanted osmotic minipumps. Because the rat central nervous system is relatively immature at birth and continues to develop for several weeks afterwards, rats will be exposed to buprenorphine at different times to determine the effect of the drug at different stages of development. It is important to study multiple doses as buprenorphine has a bell-shaped dose-response curve. Methadone exposed groups will be included as positive controls. Female rats will be implanted with a 28-day osmotic minipump containing water, buprenorphine, or methadone on day 8 of pregnancy. Pups will be cross-fostered to mothers who have been implanted with water or buprenorphine pumps. Levels of buprenorphine and its metabolite will be measured in the brains of fetuses and pups by gas chromatography/mass spectrometry. Effects of perinatal buprenorphine exposure will be determined on behavior, brain regional acetylcholine (ACh), dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites in neonatal (4 day), weanling (21 day), and adult (90 day) female and male rats. Dose-related effects of perinatal buprenorphine will be studied on brain regional endogenous opioids and their receptors as well as on ACh turnover (TRACh) in weanling and adult rats. Developmental milestones and sexual maturation will be assessed. Antinociception/nociception (tail- flick, hot-plate) in the weanling and adult rats. A gas chromatographic/mass spectrometric method will be used to measure ACh and TRACh. HPLC with electrochemical detection will be used to measure DA, NE, 5-HT, and their metabolites. Beta-Endorphin-like, met- and leu- enkephalin-like, and dynorphin-like immunoreactivity will be measured by radioimmunoassay. The Kd and Bmax for mu, delta, and kappa-opioid receptors will be determined by Scatchard analysis. In the event that changes are noted in opioid receptors, mRNA for the particular receptor will be quantified. In the event that ACh content is reduced by buprenorphine, mRNA for choline acetyltransferase will be quantified by the use of Northern blots. Once the effects of perinatal buprenorphine exposure on neurochemistry and behavior are more completely understood, more efficacious therapeutic management can be developed for pregnant addicts and potentially for prevention of drug abuse in their children.