title: Fluoxetine suppresses morphine tolerance and dependence: modulation of NO-cGMP/DA/serotoninergic pathways.
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.
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
authors.forename: V P
authors.initials: VP
authors.lastname: Singh
authors.forename: N K
authors.initials: NK
authors.lastname: Jain
authors.forename: S K
authors.initials: SK
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D003864:Depression, Chemical; D003967:Diarrhea / Q000139:chemically induced; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D004361:Drug Tolerance; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009270:Naloxone; D009292:Narcotic Antagonists; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000209:etiology
chemical_list: D001120:Arginine; D006152:Cyclic GMP; D004298:Dopamine; D005473:Fluoxetine; D019331:NG-Nitroarginine Methyl Ester; D009270:Naloxone; D009292:Narcotic Antagonists; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors