Persistence of Methadone-³H and Metabolite in Rat Brain after a Single Injection and its Implications on Pharmacological Tolerance

Abstract

BECAUSE of its properties of effective suppression of opiate withdrawal symptoms for long periods, oral absorption, longer duration of action and slow excretion, methadone has been widely used for social rehabilitation and adjustment of chronic heroin users^1,2. In spite of much work^3–10, the basic mechanism of pharmacological tolerance to methadone remains obscure. The ability of metabolic inhibitors to reduce the analgesic response significantly in experimental animals, and the lack of correlation between observable morphine-like effects and drug concentrations in tissue, has led to the suggestion that a metabolite of methadone may be responsible for its effects^11–13. The recently isolated substituted pyrrolidine and pyrroline metabolites of methadone^14–17, however, have been found to be pharmacologically inactive. This study demonstrates for the first time the persistence in the rat brain of methadone and a metabolite initially in the free form and later as a protein-conjugate after a single subcutaneous injection for periods up to 3 weeks (longer periods were riot investigated). The implications of these findings on pharmacological tolerance are discussed here.