The synergistic interaction between morphine and maprotiline after intrathecal injection in rats.

BACKGROUND: Antidepressant drugs act as potent inhibitors of norepinephrine and/or serotonin reuptake and are widely used with opioids for the treatment of chronic pain. The mechanism of this increased analgesic action is unclear. We compared the antinociceptive effects of the intrathecal administration of morphine with that of a nonselective (amitriptyline) or selective (maprotiline or citalopram) antidepressant drug using the thermal withdrawal test in rats. We also investigated the possible mechanisms involved in the interactions of these drugs. METHODS: Male Wistar rats were anesthetized with sevoflurane and administered morphine and antidepressant drugs, or saline, through intrathecal injection. The antinociceptive effect was evaluated using the thermal withdrawal test before and after drug administration. The time for the withdrawal reaction was expressed as percentage of maximum possible effect (MPE). Animals were also pretreated with yohimbine (a nonselective alpha2-adrenergic antagonist) and naloxone (a nonselective opioid antagonist) for mechanism of action studies. Pharmacologic interaction was evaluated using isobolographic analysis of simultaneous administration of fixed proportions of maprotiline and morphine. RESULTS: Single intrathecal administration of morphine (2 microg), amitriptiline (125 microg), citalopram (144 microg), and maprotiline (1.25 microg) produced 51.6% +/- 8.9%, 10.3% +/- 3.2%, 33.8% +/- 5.2%, and 48.5% +/- 9.2% MPE, respectively. The antinociceptive effect of morphine was increased when combined with amitriptyline (91.3% +/- 4.6% MPE) and maprotiline (86.9% +/- 9.2% MPE) but not with citalopram (40.6% +/- 4.6% MPE). Coadministration of maprotiline increased the antinociceptive duration of morphine by 4-fold (from 120 to 480 min), which was reversed by pretreatment with the alpha-2 adrenoceptor inhibitor, yohimbine, and the mu-type opioid receptor antagonist, naloxone. Isobolographic analysis demonstrated a synergistic interaction between morphine and maprotiline. CONCLUSIONS: Selective norepinephrine reuptake inhibitors can significantly increase the intensity and duration of morphine antinociceptive activity via both alpha(2)-adrenergic and opioid receptors. This interaction was not observed with the selective serotonin inhibitor, citalopram.

Effect of p-chlorophenylalanine and alpha-methyltyrosine on the antinociceptive effect of antidepressant drugs.

The role of para-chlorophenylalanine and alpha-methyl-DL-p-tyrosine in the antinociceptive effects of the intracerebroventricular administration of the antidepressant drugs clomipramine, zimelidine, imipramine and maprotiline was studied using the acetic acid writhing test in mice. The results demonstrated an antinociceptive effect for all these antidepressants. Pretreatment with para-chlorophenylalanine significantly reduced the antinociception induced by the ED50's of imipramine and maprotiline, and did not modify the effects of zimelidine and clomipramine, pretreatment with alpha-methyl-tyrosine did not modify the antinociception induced by these drugs except maprotiline. Pretreatment with para-chlorophenylalanine plus alpha-methyltyrosine significantly reduced the antinociceptive effect of all the antidepressants tested. The main finding of the present study is that the association of para-chlorophenylalanine plus alpha-methyltyrosine reduced the antinociceptive action of all the antidepressants. This means that critical levels of both 5-HT and NA are responsible for mediating the antinociceptive effects of antidepressants on the writhing test in mice.

Tratamento ambulatorial de depressöes resistentes: infusöes venosas de antidepressivos / Ambulatory treatment of resistant depression by venous infusions of antidepressive agents

Infusöes venosas de antidepressivos é utilizada como técnica de tratamento de Depressöes resistentes, em regime ambulatorial. Em estudo aberto com 33 pacientes, procura-se verificar a eficácia e tolerância do tratamento com infusöes. Duas substâncias, clomipramina (preferentemente serotoninérgica) e Maprotilina (noradrenérgica), säo utilizadas no estudo. Modificaçäo da técnica usual, com aumento do tempo de perfusäo, e cuidados clínicos, possibilitam a aplicaçäo em regime extra-hospitalar. Os resultados indicam evoluçäo favorável em mais de 80 por cento dos casos, com baixo nível de efeitos colaterais. Seguimento de um ano é considerado.