Blood brain barrier (BBB) is immature in newborns, this immaturity can lead to increased concentration of drugs in the brain and cerebrospinal fluid (CSF). Morphine is being increasingly advocated as an analgesic in newborns. The pharmacological actions of morphine and its metabolite morphine-6-glucuronide are predominantly by its action in the central nervous system (CNS). It is not known how the morphine permeability across the BBB changes during development In the present proposal we plan to study the permeability of morphine and its metabolites across the BBB in newborns of various gestational age.
The specific aims of the present proposal are (1) to test the hypothesis that permeability of morphine across the BBB is greater in infants with low gestational age, and (2) to study the alteration in morphine metabolism and the transfer of morphine metabolites across the BBB in infants of various gestational age. In the present proposal 60 infants (20, <30 weeks; 20, 31 to 37 weeks and 20 more than 38 weeks) receiving morphine (0.1 mg/kg, iv) prior to a lumbar puncture will be enrolled for the study. Following morphine administration CSF and blood samples will be collected at 60 min. This time has been selected on the basis of preliminary experiments where the concentration of morphine and its metabolites was determined in plasma and CSF of infants using HPLC with multiwavelength forward optical detection. Morphine levels will be estimated in both serum and. CSF by HPLC and radioimmunoassay. The major morphine metabolites to be analyzed using HPLC are (a) morphine-3-glucuronide (b) morphine-6-glucuronide, (c) morphine-3-ethereal sulfate, (d) normorphine and (e) codeine. The blood/CSF ratios of morphine and its metabolites will be calculated to determine the extent of their transfer across the BBB. The present study will demonstrate whether the permeability of morphine and its metabolites across the BBB is altered in infants with low gestational age. This knowledge will help in predicting the desired and undesired effects of morphine and its metabolites in infants with low gestational age. This study will show for the first time that gestational age affects the permeability of morphine across the blood brain barrier and will assist in optimizing the dose of morphine in newborns.
