title: The synergistic interaction between morphine and maprotiline after intrathecal injection in rats.
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 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.
authors.affiliation: Programa de Pós-Graduação em Cirurgia Geral da Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Vera L A
authors.initials: VL
authors.lastname: Pettersen
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Raimundo
authors.forename: Margarete M
authors.initials: MM
authors.lastname: Trachez
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Sudo
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage*; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000639:Amitriptyline / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007278:Injections, Spinal; D008297:Male; D008376:Maprotiline / Q000008:administration & dosage*; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010146:Pain / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D013997:Time Factors; D015016:Yohimbine / Q000008:administration & dosage
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D000639:Amitriptyline; D000701:Analgesics, Opioid; D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D008376:Maprotiline; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D015016:Yohimbine