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Keywords:

  • 5-HT2A receptor;
  • cortical spreading depression;
  • medication-overuse headache;
  • paracetamol;
  • Fos;
  • trigeminal nociception

(Headache 2010;50:185-197)

Objectives.— To determine the involvement of 5-HT2A (5-HT2A) receptor in the process of trigeminal plasticity induced by chronic analgesic exposure and in the process of inflammatory-induced thermal hyperalgesia.

Background.— Derangement in 5-HT2A serotonin receptor has been reported to implicate in pathogenesis of medication-overuse headache. No clear explanation concerning the precise roles of these receptors in the process.

Methods.— Wistar rats were daily administered with paracetamol (200 mg/kg) for 30 days. On the next day, ketanserin, a 5-HT2A antagonist, or saline was given prior to cortical spreading depression (CSD) induction. Electrocorticogram, cortical blood flow, Fos and 5-HT2A-immunoreactivity in cortex and trigeminal pathway were studied. In the other experiment, complete Freund's adjuvant was injected into the rat hind paw to induce tissue inflammation. Three days later, ketanserin was given and noxious heat was applied to both inflamed and noninflamed paws. The response between 2 sides was compared by measuring paw withdrawal latency.

Results.— Chronic paracetamol exposure led to an increase in CSD frequency and CSD-evoked Fos expression in cerebral cortex indicating the increase in neuronal excitability. Prolonged medication exposure also facilitated trigeminal nociception as evident by an increase in CSD-evoked Fos expression in trigeminal nucleus caudalis. The expression of 5-HT2A receptor in cerebral cortex and trigeminal ganglia was enhanced by chronic paracetamol administration. Pretreatment with ketanserin significantly attenuated these effects. The second experiment showed that ketanserin was able to lengthen the paw withdrawal latency in the inflamed side but did not alter nociceptive response in the noninflamed side.

Conclusion.— These findings suggest that up-regulation of pro-nociceptive 5-HT2A receptor is an important step in the process of cortical hyper-excitation and nociceptive facilitation induced by chronic analgesic exposure.