title: Serotonin depletion leads to cortical hyperexcitability and trigeminal nociceptive facilitation via the nitric oxide pathway.
abstract: OBJECTIVE
  To investigate the role of nitric oxide (NO) in the development of cortical hyperexcitability and trigeminal nociceptive facilitation induced by serotonin (5-HT) depletion.
  
  
  BACKGROUND
  Nitric oxide and 5-HT are important in the pathogenesis of primary headaches. An increase in cortical excitability and trigeminal nociception has been demonstrated in animals with low 5-HT levels. Although the mechanism underlying this increase is unclear, an alteration of the NO system is one possible explanation.
  
  
  METHODS
  Male Wistar rats were divided into control and 5-HT-depleted groups. 5-HT was depleted by i.p. injection of parachlorophenylalanine (100 mg/kg). Three days after injection, a microelectrode was inserted into the cerebral cortex for electrocorticograph recording and waves of cortical spreading depression (CSD) were triggered with KCl application. N-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg by i.v. injection) or saline was given after the second CSD wave. Following the experiment, the cerebral cortex and brain stem were removed for anti-neuronal nitric oxide synthase (nNOS) and anti-Fos immunohistochemistry.
  
  
  RESULTS
  Relative to the control group, the 5-HT-depleted group exhibited a higher frequency of CSD waves, more nNOS-immunoreactive cells in both the cerebral cortex and brainstem and more Fos-immunoreactive cells in the trigeminal nucleus caudalis (TNC). In the control group, L-NAME application led to fewer nNOS-immunoreactive cells in the cerebral cortex and TNC, and fewer Fos-immunoreactive cells in the TNC; however, L-NAME was without effect on the CSD pattern. By contrast, in addition to decreased nNOS and Fos expression, L-NAME significantly reduced the frequency of CSD events in the 5-HT-depleted group.
  
  
  CONCLUSIONS
  Inhibition of NO production can counter both the cortical hyperexcitability and facilitation of trigeminal nociception that develop in the depleted 5-HT state. Therefore, NO is likely involved in the increase in both CSD events and CSD-evoked trigeminal nociception under decreased 5-HT conditions.
authors.affiliation: Department of Pathology, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Patumwan, Bangkok, Thailand.
authors.forename: Supang Maneesri
authors.initials: SM
authors.lastname: le Grand
authors.forename: Weera
authors.initials: W
authors.lastname: Supornsilpchai
authors.forename: Chonlawan
authors.initials: C
authors.lastname: Saengjaroentham
authors.forename: Anan
authors.initials: A
authors.lastname: Srikiatkhachorn
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000172:deficiency*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014276:Trigeminal Nerve / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D016760:Proto-Oncogene Proteins c-fos; C073090:chlormethamphetamine; D009569:Nitric Oxide; D012701:Serotonin; D008694:Methamphetamine; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester