Studies on the Physical Dependence Liability of Analgesics

Abstract

Abstract-Influence of codeine on the fine structure of mitochondria in the cells of zona fasciculata of rat adrenal cortex was studied electronmicroscopically. By the administration of codeine in a dose of 40 mg/kg, the number of intramitochondrial vesicles was decreased, the change being diminished during repeated administration of the drug. Withdrawal of codeine reproduced an extensive transformation, while with a re-injection of the drug, a prompt restoration to the pretreated structure was observed. The feasibility of utilizing this transformation as an index of physical dependence liability has been discussed.It has been evidenced that abrupt withdrawal of morphine or levallorphan challeng ing produces a marked transformation of ultrastructure of zona fasciculata mitochondria in adrenal cortex of the morphine addicted rats (1) and the time course of appearance of the transformation is in close agreement with that of loss in body wt. after withdrawal, this being the best index of physical dependence liability. On the other hand, CG-315, a newly synthesized analgesic, shows neither the mitochondrial transformation nor fall in body wt. after withdrawal of the drug during chronic administration (2, 3).The present experiments were undertaken to clarify whether codeine with moderate physical dependence liability (4, 5) is able to produce the mitochondrial transformation after withdrawal.MATERIALS AND METHODS Unless otherwise noted, the experimental rat strain, feeding condition and procedures for electron-microscopic examination were the same as described in the first report (1).In chronically administered experiments, rats were given four s.c. injections of codeine daily 6 hr intervals (6 a.m., noon, 6 p.m. and midnight) for 50 days. The initial dose of the drug was 20 mg/ kg/day during the first week (5 mg/kg x 4 daily), 40 mg/kg in the second week, 60 mg/kg in the third week, 80 mg/kg in the 4th week and 100 mg/kg in the 5th week until sacrifice.

STUDIES ON THE PHYSICAL DEPENDENCE OF A NEW CENTRAL ANALGESIC; 1-(m-METHOXYPHENYL)-2-DIMETHYLAMINOMETHYL CYCLOHEXANOL (1) HCL (CG-315)

“…This result relates to the findings reported by Yano et al (18,19) that morphological changes of the mitochondria in adreno-cortical cells of rats treated with repeated injections of morphine after abrupt withdrawal were apparently observed, however, this was not the case with the CG-315 chronically-treated rats. …”