Fluoxetine suppresses morphine tolerance and dependence: modulation of NO-cGMP/DA/serotoninergic pathways

Methods Find Exp Clin Pharmacol. 2003 May;25(4):273-80. doi: 10.1358/mf.2003.25.4.769675.

Abstract

Although the phenomenon of opioid tolerance and dependence has been widely investigated, neither opioid nor non-opioid mechanisms are completely understood. In view of the modulation of 5-HT transport into presynaptic terminals in the brain by nitric oxide (NO) via cGMP, and the existence of a tonic 5-HTergic inhibition of dopamine release, the present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, and NO modulators L-N(G)-nitroarginine methyl ester (L-NAME; NO synthase inhibitor) and L-Arginine (substrate for nitric oxide synthase) alone or in combination against morphine tolerance and dependence. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg s.c. twice daily) on day 3 and the degree of tolerance was further enhanced on days 9 and 10. The development of tolerance to the antinociceptive effect of morphine was delayed by prior administration of fluoxetine (10 mg/kg i.p, twice daily for 9 days) and L-NAME (10 mg/kg i.p. twice daily for 9 days) alone or in combination. It was accentuated by L-Arginine (50 mg/kg i.p. twice daily for 9 days) alone or in combination with fluoxetine (10 mg/kg i.p. twice daily for 9 days). Similarly, fluoxetine (10 mg/kg i.p.) or L-NAME (10 mg/kg i.p.), when administered acutely on day 10, reversed morphine-induced tolerance. L-Arginine (50 mg/kg i.p.) however, when administered acutely on day 10, accentuated morphine tolerance. Fluoxetine (10 mg/kg i.p. twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg i.p.)-precipitated withdrawal jumps. This suppression of dependence was potentiated by L-NAME (10 mg/kg i.p. twice daily for 9 days) and reversed by L-Arginine (50 mg/kg i.p. twice daily for 9 days), respectively. Acute administration of the respective drugs on day 10 modulated morphine dependence in a similar fashion. L-Arginine also reversed fluoxetine-induced weight loss in morphine-dependent animals. The present study demonstrated that fluoxetine suppressed the dependence and development of tolerance to the antinociceptive effect of morphine. Fluoxetine-induced suppression was potentiated by L-NAME and accentuated by L-Arginine. The results therefore suggest that a complex phenomenon such as morphine tolerance and dependence might involve close interplay of the NO-c GMP/5-HT/DA receptor system. To the best of the authors' knowledge, this is the first report to suggest targeting this cascade for amelioration of opioid tolerance and withdrawal syndrome.

MeSH terms

  • Animals
  • Arginine / pharmacology
  • Body Weight / drug effects
  • Cyclic GMP / metabolism*
  • Depression, Chemical
  • Diarrhea / chemically induced
  • Dopamine / metabolism*
  • Drug Interactions
  • Drug Tolerance*
  • Female
  • Fluoxetine / pharmacology*
  • Male
  • Mice
  • Morphine Dependence / metabolism*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Naloxone
  • Narcotic Antagonists
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Serotonin / metabolism*
  • Serotonin Uptake Inhibitors / pharmacology*
  • Substance Withdrawal Syndrome / etiology

Substances

  • Narcotic Antagonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Nitric Oxide
  • Serotonin
  • Naloxone
  • Arginine
  • Nitric Oxide Synthase
  • Cyclic GMP
  • NG-Nitroarginine Methyl Ester
  • Dopamine