The role of 5-HT1B/1D and 5-HT2A/2C receptors in neurovascular response to nitric oxide in rat trigeminovascular system

Abstract

This study was conducted to investigate the effect of two serotonin receptor subtypes, namely 5-HT1B/1D and 5-HT2A/2C receptors on the cerebrovascular nociception. Adult male Wistar rats were divided into four groups, including those pretreated with sumatriptan, naratriptan, 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and physiologic saline. Sumatriptan or naratriptan were used as 5-HT1B/1D agonist whilst DOI was employed to activate the 5-HT2A/2C receptor. The measured parameters included regional cerebral blood flow (rCBF) and neuronal nitric oxide synthase (nNOS) expression. The change in rCBF was monitored using laser Doppler flowmetry. The degree of nNOS expression was quantitated at the trigeminal ganglion, trigeminal nucleus caudalis and perivascular nerve fiber by immunohistochemical method. The results showed that neither sumatriptan nor naratriptan altered the rCBF. On the other hand, administration of DOI could significantly increase the basal rCBF. To study the effect of these receptor agonists on nitric oxide (NO)-induced change in trigeminovascular system, nitroglycerin was intravenously infused to the animals. The results showed that exposure to NO-donor led to a long-lasting cerebral hyperemia. It was also demonstrated that despite the lack of their efficacy in altering the basal rCBF, pretreatment with 5-HT1B/1D agonists could minimize the degree of NO-induced hyperemia in cerebral cortical tissue. No significant change was observed in the group pretreated with DOI as compared with those receiving nitroglycerin alone. The immunohistochemical study showed that exposure to NO-donating agent could induce expression of nNOS system in various structures of the trigeminovascular pathway. The surface area of nNOS-IR perivascular varicosity around the superior sagittal sinus was greater in the nitroglycerin-treated animals. The number of nNOS-IR neurons in trigeminal ganglion and trigeminal nucleus caudalis were also greater in this group. Pretreatment with 5-HT1B/1D agonist, sumatriptan can attenuate the NO-evoked nNOS expression in all areas. It was also showed that administration of DOI could induce nNOS-IR in these strutures but did not interfere with the effect of NO in the activation of nNOS. Based on these findings, it can be concluded that administration of nitroglycerin or DOI results in long-lasting vasodilation by activating the endogenous nNOS system. The effect of NO in induction of vasodilatation and nNOS expression can be attenuated b prior activation of 5-HT1B/1D receptor. These results indicate that different serotonin receptors exert different role in control of cerebrovascular nociception