Transport in the Central Nervous System

Abstract

Most of the prominent and important effects of narcotic analgesics on the body are a result of their action in the central nervous system (CNS). The sites and mechanisms of action of these drugs in the nervous system are unknown. One approach to identifiying a site or mechanism of action of a drug is to study its distribution within the responsive tissues. In the case of the narcotic analgesics the significance and specificity of sites of drug localization in the CNS can be evaluated by correlating the rise and fall of drug concentration at various sites with the onset and duration of pharmacological actions (for example, analgesia), by studying the effects of narcotic antagonists (for example, nalorphine or naloxone) on the distribution of the drug, and by determining the effects of tolerance development on the tissue concentrations of narcotic analgesics. This approach to identifying a site of narcotic action in the nervous system has proven to be unrewarding in the intact animal (for example, see Mule et al.,(1, 2, 7) Hug et al.,(3, 4) Johannesson et al.,(5, 6) and Chernov and Woods(8) and see Way and Adler(9) for earlier references). First, unique sites of localization were not detected. Second, changes in localization induced by nalorphine or tolerance development were small, often neither biologically nor statistically significant. Third, in the intact animal there are numerous factors that influence the uptake of drugs by the nervous system, and the reproducibility and interpretation of experiments thereby are made difficult. Finally, the techniques employed would not be likely to detect sites of localization at the cellular or subcellular levels.