Proceedings: Stereospecific suppression by opiates of the quasi-morphine abstinence syndrome elicited by 3-isobutyl-l-methylxanthine (IBMX).

Methylxanthines elicit from otherwise untreated rats several of the behavioural signs seen in the morphine abstinence syndrome (MAS). Heroin readily suppresses the signs elicited by methylxanthines, and naloxone increases their intensity and elicits other signs, such as jumping, to produce a behavioural pattern scarcely distinguishable from the MAS (Collier, Francis, Henderson & Schneider, 1974; Francis, Roy & Collier, 1975). We have, therefore, called the behaviour elicited by xanthines the quasimorphine abstinence syndrome (QMAS). The present work examines whether suppression by opiates of the QMAS is stereospecific and whether drugs modifying it are effective when injected into a cerebral ventricle. Drugs were injected into male white Wistar rats (1 10-200 g) either subcutaneously (s.c.) or, through an indwelling cannula, into the left lateral cerebral ventricle (i.c.v.). The QMAS was elicited with 3-isobutyl-l -methylxanthine (IBMX, 15 mg/kg s.c.) and effects on behavio observed 'blind' for up to 15 mirm after treatment with coded solutions. Fourteen behavioural signs -jumping, teeth chattering, squeak on touch, squeak on handling, diarrhoea, chewing, ptosis, body shakes, head shakes, paw tremor, rearing, restlessness, salivation and licking the penis-were recorded. Total 'quasi-abstinence score' was obtained by counting 1 for presence and 0 for absence of each sign, and was expressed as a median value. The significance of differences between scores was determined by the MannWhitney U test. Heroin (30-300 fg/kg s.c. or 1 and 10 gg/rat i.c.v.) overcame the QMAS in a dose-related way. When the QMAS had been suppressed with heroin (300 jig/kg s.c.), naloxone (10-100,jg/kg s.c. or 0.1-1Ojg/rat i.c.v.) reversed the suppression in a dose-related way. Levorphanol (10-100 ,ig/kg s.c.) also suppressed the QMAS; but dextrorphan was ineffective at 8 mg/kg s.c. These effects were statistically significant at P values ranging downwards from P = 0.027 to P < 0.001. That the potent effect of opiates in overcoming the QMAS due to IBMX is stereospecific and is reversed by very small doses of naloxone shows that this is an opiate agonist action. Methylxanthines in turn antagonize opiate agonist actions (Bellville, 1964; Ho, Loh & Way, 1973). This mutual antagonism may provide a clue to the mechanisms of action of both types of drug and to the mechanisms of dependence. These findings also offer a sensitive in vivo method of detecting and estimating the behavioural effects of morphine-like, methylxanthine-like or naloxone-like substances.