Transport of narcotic analgesics by choroid plexus and kidney tissue in vitro

Abstract

Radioactive narcotic analgesics, including morphine, dihydromorphine, nalorphie, codeine, levorphan, dextrorphan, and I-methorphan were accumulated against an apparent concentration gradient in pieces of rabbit and dog choroid plexus and in slices of dog renal cortex by a metabolically depsndent mechanism. The uptake of dihydromorphine by these tissues in vitro was a saturable process depressed by low temperatures, a nitrogen atmosphere, and certain metabolic inhibitors. It also was competitively inhibited by nalorphme and by any one of several organic bases which previously have been demonstrated to be actively transported by these tissues. Under certain conditions, stimulation of ~hydromo~hine uptake by choroid plexus was produced by organic bases. The transport in choroid plexus of one of these organic bases, hexamethonium, was competitively inhibited by dihydromorphine. Studies with levorphan and dextrophan indicated an element of stereospecificity in their accumulation by choroid plexus. Thus it is concluded that the narcotic analgesics share the same active transport mechanisms described for a variety of organic bases that are accumulated in choroid plexus and renal tissue in vitro. Suggestions are made relative to the significance of these observations for the intact animal.

Characterization of (±)‐methadone Uptake by Rat Lung

“…A variable degree of inhibition of the active transport of different compounds (morphine, dihydromorphine, 5-HT, NA, etc.) by iodoacetate has been observed by other investigators (Takemori & Stenwick, 1966;Hug, 1967;Rubin, Owens & Rall, 1968;Iwasawa et al, 1973). One should, therefore, be careful in interpreting results obtained by using iodoacetate as a tool to evaluate the energy requirements or dependency of a transport process.…”

“…When investigating the uptake of morphine by choroid plexus, Takemori & Stenwick (1966) observed that as the pH of the incubation medium was varied from 6.5 to 7.5, the T/M ratio of morphine increased from 2.5 to 9.0 and beyond the pH of 7.5 there was no further increase in the T/M ratio. It was observed by Hug (1967) that varying the pH of the medium over the range of 6.8-8.0 produced no consistant effect on the uptake (T/M ratio) of dihydromorphine by choroid plexus. These investigators were unable to draw any definite conclusions as to why the uptake of morphine was facilitated with increasing pH but that of dihydromorphine was unaffected.…”

“…Although Orton et aL (1973) investigated the uptake of (±)-methadone by isolated perfused lung of rabbit, data on stereospecificity were not reported. However, Hug (1967) demonstrated that the in vitro rate of uptake of dextrorphan by the rabbit choroid plexus was greater than that of levorphan. He suggested that the transport mechanism was the same for either compound, but the relative affinity of dextrorphan and levorphan were different.…”

“…Iodoacetate is such a metabolic inhibitor that produces its effect through alkylation of -SH groups of enzymes, particularly those that are involved in the glycolytic pathway (Webb, 1963). Dixon (1937) (Takemori & Stenwick, 1966;Hug, 1967;Rubin, Owens & Rall, 1968;Iwasawa et al, 1973). One should, therefore, be careful in interpreting results obtained by using iodoacetate as a tool to evaluate the energy requirements or dependency of a transport process.…”

Respiratory Depressant Effects of Morphine on the Central Nervous System of the Infant Rat

“…However, at doses of 0.1 mg/kg, having no observable effect on the respiratory rate of the infant rat, morphine concentrations in the cerebrospinal fluid did not increase with rising blood levels, maintaining values that were lower than brain stem concentrations. At non-respiratory depressant doses, morphine is eliminated from the cerebrospinal fluid system to the peripheral circulation by the mechanisms of bulk flow [2] and active transport at the choriod plexus [1,8,16], The infant rat has an extremely sluggish rate of bulk flow associated with a decreased rate of cerebrospinal fluid formation by the poorly differentiated epithelial cells of the choroid plexus [2]. Additionally, the present data suggest that at respira tory depressant doses, the mechanism in the choroid plexus for the active transport of morphine to the peripheral circulation may be saturated, resulting in accumulation of the drug in the cerebral ventricles allowing its direct penetration into brain stem respiratory centers.…”