Active uptake of dihydromorphine and other narcotic analgesics by cerebral cortical slices.

Narcotic analgesics have been shown to be accumulated in cerebral cortical slices by a process having the characteristics of an active transport system. In addition, diffusion and binding contributed to the total uptake of the analgesics into brain slices. The total uptake of dihydromorphine (1 x 10-e M in medium) was found to reach steady state equilibrium in 30 min at 37” with a maximum tissue to medium concentration ratio (T/M) of 2.3. Accumulation in vitro of the narcotic analgesics in brain differed from their accumulation in the kidney and in the choroid plexus in that there was a lower T/M ratio at equilibrium for brain and the uptake by brain was not inhibited by quatemary organic bases. The narcotic analgesic antagonist, nalorphine, consistently depressed the uptake of dihydromorphine in a competitive manner. NARCOTIC analgesics have been shown to be taken up by the kidneyiand choroid plexusa~ 4 by active transport processes. It has been suggested that transport of these drugs by the choroid plexus may facilitate their removal from cerebrospinal fluid?* 4 just as their transport by the kidney promotes their elimination from the body.13 s Upon administration of an analgesic dose, the central nervous system is the site of the most prominent effects of the narcotic analgesics. The central nervous system is known to have transport processes for the uptake and elimination of a variety of endogenous and exogenous substances. 5,s The transport systems are thought to affect the concentration of these substances in certain cellular and subcellular compartments.? The present study was undertaken to determine if the narcotic analgesics interact with the transport systems of brain tissue. Such interaction could have signifrcant implications for the distribution of these drugs in nervous tissue and for their pharmacological alteration of central nervous system function. MATERIALS AND METHODS Preparation of slices. Male Holtzman rats (150-200 g) were sacrificed by decapitation. The brain was removed, cut longitudinally into hemispheres and cerebral cortical slices (1040 mg) were cut freehand starting at the outer cortical surfaces by the method of McIl\;vain and Rodnight. In order to avoid inclusion of white matter, only two slices were taken from each hemicortex of the rat; thus, in some experiments each * A summary of the work presented in detail here appeared in The Pharmacologist 9,218 (1967). ILtizte of Mental Health. is investigation was supported in part by Research Grant MH-08580 from the National