The effects of chronic administration of sumatriptan and dipyrone on serotonergic system in the rat brain: an immunohistochemical study Introduction Excessive use of medications leads to transforma- tion of migraine or tension-type headache to a chronic daily or near-daily headache pattern which is classified under the title of Ômedication overuse headacheÕ (MOH) according to the classification scheme of the International Headache Society (1). All antiheadache drugs were demonstrated to induce MOH including symptomatic drugs, such as analgesics, opioids, barbiturates, ergots (2–4) and triptans (3, 5, 6). In a recent longitudinal population-based study, Bigal et al. (7) demon- strated that triptans and non-steroidal antiinflam- matory drugs (NSAIDs) were not associated with an increased risk of transformed migraine. How- ever, for the NSAIDs this relationship was dem- onstrated only in patients with low or intermediate but not with high frequency of headaches. The authors stressed the need for being cautious about using any medication in individuals with a high frequency of headache. The pathophysiological mechanisms underlying MOH are still insufficiently understood (8). Decrease in blood serotonin levels that leads to upregulation of pain receptors plays a key role among pathophysiological mechanisms of MOH (8, 9). Investigations have suggested that a decrease in blood serotonin levels may be caused by chronic use of symptomatic medications that may indirectly lead to increased headache due to a corresponding upregulation of 5HT2 receptors in the brain (10, 11). Based on evidence from animal studies, chronic analgesic administration increases the number of 5HT receptors both in the cortex and pons (12). This finding was further supported with recent human studies in which platelets had been used as a neuronal model, assuming that platelets were the representative of central serotonergic neurons (8, 13–15). Dipyrone, a pyrazole-derived compound, Acta Neurol Scand 2009: 120: 264–269 DOI: 10.1111/j.1600-0404.2008.01153.x Copyright Ó 2009 The Authors Journal compilation Ó 2009 Blackwell Munksgaard ACTA NEUROLOGICA SCANDINAVICA Genc¸ E, Avunduk MC, Og˘uz Genc¸ B, Saide S¸ahin A, O ¨ z M. The effects of chronic administration of sumatriptan and dipyrone on serotonergic system in the rat brain: an immunohistochemical study. Acta Neurol Scand 2009: 120: 264–269. Ó 2009 The Authors Journal compilation Ó 2009 Blackwell Munksgaard. Objective – To investigate the effects of chronic high dose sumatriptan and dipyrone treatment on central serotonergic system in rats. Materials and methods – Male Sprague–Dawley rats (seven per group) were daily injected with sumatriptan (3 mg ⁄ kg), dipyrone (400 mg ⁄ kg) or saline for 30 days. The brains of animals were surgically removed and immunohistochemically stained for serotonin. Serotonin-positive stained cells were counted automatically by using a computerized image analysis program. Statistical analysis carried out using one-way ANOVA followed by post hoc Tukey test. Results – A significant decrease in serotonin-positive cells in the brainstem was observed after chronic sumatriptan administration while chronic use of dipyrone induced a significant increase in serotonin-positive cells both in the cortex and midbrain. Conclusion – Our data suggest that central serotonergic system might be modified by chronic use of sumatriptan and dipyrone. E. GenÅ 1 , M. C. Avunduk 2 , B. Og ˘uz GenÅ 1 , A. Saide S ¸ ahin 3 , M. Öz 4 Departments of 1 Neurology, 2 Pathology, and 3 Pharmacology, Meram School of Medicine, Selcuk University, Konya, Turkey; 4 Experimental Medicine and Research Center, Meram School of Medicine, Selcuk University, Konya, Turkey Key words: dipyrone; immunohistochemical staining; rat; serotonin expression; sumatriptan Emine GenÅ, Department of Neurology, Meram School of Medicine, Selcuk University, 42080 Konya, Turkey Tel.: +90 332 2236260 Fax: +90 332 3232641 e-mail: eminegencduran@gmail.com Accepted for publication November 12, 2008 264