Serotonin Depletion Leads to Cortical Hyperexcitability and Trigeminal Nociceptive Facilitation via the Nitric Oxide Pathway

Authors

  • Supang Maneesri le Grand PhD,

    1. From Department of Pathology, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand (S.M. le Grand and C. Saengjaroentham); Departments of Physiology, Faculty of Dentistry, Chulalongkorn University, Patumwan, Bangkok, Thailand (W. Supornsilpchai); Department of Physiology, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand (A. Srikiatkhachorn).
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  • Weera Supornsilpchai PhD,

    1. From Department of Pathology, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand (S.M. le Grand and C. Saengjaroentham); Departments of Physiology, Faculty of Dentistry, Chulalongkorn University, Patumwan, Bangkok, Thailand (W. Supornsilpchai); Department of Physiology, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand (A. Srikiatkhachorn).
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  • Chonlawan Saengjaroentham BSc,

    1. From Department of Pathology, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand (S.M. le Grand and C. Saengjaroentham); Departments of Physiology, Faculty of Dentistry, Chulalongkorn University, Patumwan, Bangkok, Thailand (W. Supornsilpchai); Department of Physiology, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand (A. Srikiatkhachorn).
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  • Anan Srikiatkhachorn MD

    Corresponding author
      A. Srikiatkhachorn, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Patumwan, Bangkok 10330, Thailand.
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  • Financial support: This study was supported by grants from the Thailand Research Fund (Grant Number MRG 4880093 and RTA 518004).

  • Conflict of Interest: None

A. Srikiatkhachorn, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Patumwan, Bangkok 10330, Thailand.

Abstract

(Headache 2011;51:1152-1160)

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.

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