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ANALGESIA

The Synergistic Interaction Between Morphine and Maprotiline After Intrathecal Injection in Rats

Vera L. A. Pettersen, MD^*, Gisele Zapata-Sudo, MD, PhD, Juliana M. Raimundo, PhD, Margarete M. Trachez, MD, PhD, and Roberto T. Sudo, MD, PhD

From the *Programa de Pós-Graduação em Cirurgia Geral da Universidade Federal do Rio de Janeiro; Programa de Desenvolvimento de Fármacos do Instituto de Ciências Biomédicas da Universidade Federal do Rio de Janeiro; and Serviço de Anestesiologia da Universidade Federal Fluminense, Rio de Janeiro, Brazil.

Address correspondence and reprint requests to Roberto Takashi Sudo, MD, PhD, Centro de Ciências da Saúde, Bloco J, Sala 14, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas 373, Cidade Universitária, Rio de Janeiro 21941-590, Brazil. Address e-mail to rtsudo{at}farmaco.ufrj.br.

Abstract

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 µg), amitriptiline (125 µg), citalopram (144 µg), and maprotiline (1.25 µg) 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 -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 ₂-adrenergic and opioid receptors. This interaction was not observed with the selective serotonin inhibitor, citalopram.