Pharmacokinetic patterns of repeated administration of antidepressants in animals. II. Their relevance in a study of the influence of clomipramine on morphine analgesia in mice

Many studies have shown tricyclic antidepressants (TCAs) to potentiate morphine analgesia, but more recent work, using different modes of administration, has revealed inhibition of morphine analgesia by TCAs. The influence of different modes of administration of clomipramine (CMI) on morphine analgesia assessed by the hot-plate test was studied in mice. The administration procedure was based on the pharmacokinetic parameters of CMI determined in the strain used. Acute and chronic (i.e., every half-life of 130 min for five half-lives) administration of CMI (10 or 20 mg/kg i.p.) had opposite effects; the former potentiated morphine analgesia and the latter inhibited it. Five closely repeated administrations (i.e., every 40 min) suppressed the potentiation without producing inhibition. The time course of the influence of CMI showed that the inhibition of morphine analgesia observed after repeated administration of a given dose of CMI occurred if the latter was present for sufficient time; this time decreased when the dose of CMI was increased. Moreover, comparison with literature data shows the importance of standardized patterns of repeated administration: the variability in the frequency of repeated administration and in the time-lag between the last injection of TCA and the test may account for the varying results observed. The discrepancies in the literature regarding TCA/morphine interaction are thus only apparent, and arise merely from varying conditions. Possible mechanisms for the CMI-morphine interaction are discussed: involvement of opiate receptors and/or the serotonergic system.