Effect of paracetamol on cortical spreading depression, trigeminal nociception and 5-HT[subscript 2A] receptor expression

Abstract

The present study aims to investigate the effect of acute and chronic paracetamol administration on trigeminal nociception. The study comprised two experiments based on acute and chronic paracetamol administration. In acute experiment, the rats were divided into paracetamol-treated and control groups (8 rats each). A single dose of paracetamol (200 mg/kg BW, intraperitonealy) was given to the treatment group whereas vehicle (12.5% of 1,2-propane-diol in 0.9% sterile saline) was given to the control group. Trigeminal nociception was evoked by cortical spreading depression (CSD) using topical KCl application. CSD was elicited at 60 minute after paracetamol injection. In chronic paracetamol experiment, the rats were divided into paracetamol treated and control groups. Paracetamol (200 mg/kg BW, intraperitonealy) or vehicle was injected once daily for the period of 30 days. Electrocorticogram was measured continuously for one hour using glass microelectrode. Cortical blood flow was monitored using Doppler flowmetry. Expression of immediate early gene product, Fos, was used as a indicator of neuronal activity. The 5-HT[subscript 2A] receptor and Fos expression were studies by immunohistochemistry. The change of endothelial cell was studied by electron microscopy. The results showed that cortical application of KCl resulted in a series of depolarization shift which coincided with cortical hyperemia and Fos expression in the TNC. Acute treatment with paracetamol significantly attenuated the CSD-evoked hyperemia and number of Fos-immunoreactive cells in the TNC without changes in the CSD frequency. On the other hand, chronic paracetamol administration substantially increased the CSD frequency, number of Fos-immunoreactive cells in the cortex and TNC, indicating the increase in cortical excitability and trigeminal activation. In addition, the EM studies showed that chronic paracetamol exposure may interfere with the cerebral microvascular permeability as evident by an increase in CSD-evoked pinocytosis and microvillous formation. To investigate the involvement of serotonin system in this process, ketanserin, a 5-HT[subscript 2A] antagonist was given to the rats prior to CSD. We found that pretreatment with ketanserin can decrease the frequency of CSD and can inhibit the expression of Fos both in cortex and the TNC. The results of the present study indicate that chronic paracetamol exposure can lead to an increase in neuronal excitability in both cerebral cortex and the pain processing pathway. The mechanism of this hyperexcitability may involve the alteration of central serotonin system. These observations provide better understanding regarding the pathogenesis of medication-induced headache and may shed light for future pharmacologic intervention.