Blood-Brain Barrier: Penetration of Morphine, Codeine, Heroin, and Methadone after Carotid Injection

Abstract

Labeled morphine, codeine, heroin, or methadone was injected as a bolus into the common carotid artery of the rat, and the rat was decapitated 15 seconds later. The brain uptake of the drug was calculated by measurement of the brain content of the drug as a percentage of a labeled, highly diffusible reference substance simultaneously injected. The uptake of morphine was below measurability; the uptake of codeine was 24 percent; heroin, 68 percent; and methadone, 42 percent. Brain uptakes of morphine and codeine were also studied after intravenous injection and correlated well with uptakes after carotid injection; the uptake of codeine being nearly complete by 30 seconds. These studies indicate that brain uptake of certain of these drugs is very rapid and that uptake of heroin injected intravenously is probably limited by the regional flow of blood in the brain. The possible relation of this rapid penetration of the blood-brain barrier by heroin to its strongly addictive properties is discussed.

Clonidine Transport at the Mouse Blood—Brain Barrier by a New H+ Antiporter that Interacts with Addictive Drugs

“…Although morphine inhibits the transport of clonidine, its substrate capacity for an influx BBB carrier process could not be suggested (Cisternino et al, 2004). Moreover, morphine is poorly transported at the rodent's BBB, even after the P-gp efflux is inhibited (Cisternino et al, 2004;Oldendorf et al, 1972). These observations suggest that morphine is probably not an efficient substrate of this amines/H + antiporter, unlike oxycodone (Okura et al, 2008).…”

“…These observations suggest that morphine is probably not an efficient substrate of this amines/H + antiporter, unlike oxycodone (Okura et al, 2008). Although little differences exist in the molecular structure between morphine, codeine, and heroin (diacetylmorphine), it was postulated that the great differences in the brain uptake of these cationic drugs are due to their passive permeability at the BBB (Oldendorf et al, 1972). Although a wide range of CNS drug interactions is illustrated in our study, a general feature of the compounds that interfere with clonidine transport is that they have an aliphatic secondary or tertiary amine moiety linked through a chain containing 1 to 4 atoms (carbon and/or heteroatoms) to a planar aromatic structure (phenyl, pyridine).…”

Acute and chronic heroin dependence in mice: Contribution of opioid and excitatory amino acid receptors

“…Despite their differences, the heroin-naloxone interval yielding maximal responses after acute (2 h) and chronic (1h) heroin are still smaller than those demonstrated for acute (3h) and chronic (3h) morphine treatment (Wiley and Downs, 1979;El-Kadi and Sharif, 1994). It seems logical to us that ability of heroin to more rapidly cross the blood-brain barrier and penetrate the brain relative to morphine (Oldendorf, 1972) may underlie this difference.…”

Characterization of Dextromethorphan and Dextrorphan Uptake by a Putative Glutamic Acid Carrier and Passive Diffusion across Brain Microvessel Endothelium

“…In the heroin-morphine model, masking of hydroxyl groups on morphine with either one acetyl group (i.e., codeine) or two acetyl groups (i.e., heroin) allows enhanced passive permeation across the BBB (27). The removal of the single methyl group from DM to form DX also seems to have limited the availability for transcellular passage and in the process enhanced BMEC binding.…”