900 0097-0549/20/5007-0900 ©2020 Springer Science+Business Media, LLC Neuroscience and Behavioral Physiology, Vol. 50, No. 7, September, 2020 Mast Cell Mediators as Pain Triggers in Migraine: Comparison of Histamine and Serotonin in the Activation of Primary Afferents in the Meninges in Rats D. F. Nurkhametova, 1,2 K. S. Koroleva, 1,2 O. Sh. Gafurov, 1 R. R. Giniatullina, 2 G. F. Sitdikova, 1 and R. A. Giniatullin 1,2 Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 105, No. 10, pp. 1225–1235, October, 2019. Original article submitted July 2, 2019. Revised version received July 19, 2019. Accepted July 19, 2019. The meninges around the brain are characterized by an abundant blood supply, a high density of sensory nerves, and large numbers of mast cells. In migraine, the commonest neurological disorder, activation of tri- geminal nerve fibers in the meninges is the initial trigger mechanism for generating pain signals. The recent- ly suggested concept of the neuroimmune synapse suggests that mast cell transmitters can activate receptor proteins in close-lying nerve endings, leading to the generation of nociceptive spike activity. Serotonin and histamine, presumptive triggers for migraine, are classical transmitters released on activation of mast cells. Our recent research has identified powerful activation of primary afferents by serotonin, mediated mainly via 5-HT 3 receptors. However, the role of histamine in meningeal neuroimmune synapses has received little study. The present study therefore used recording of spike activity from primary afferents in the meninges in rats to study the role of histamine as a possible trigger for pain in migraine. Results from testing a wide range of histamine concentrations identified only a minimal (about 12%) effect with 10 μM histamine on the nociceptive activity of the trigeminal nerve. More detailed cluster analysis showed that the proportion of fibers reacting to histamine was no more than 29%, increases in spike activity in these fibers being signifi- cantly lower than on exposure to serotonin. Longer (4 h) exposure to histamine also produces no significant change in trigeminal nerve activity. The results do not exclude a stimulatory role for histamine in migraine but suggest that this mast cell transmitter has an action other than activation of the trigeminal nerve. Keywords: migraine, nociception, trigeminal nerve, action potential, histamine, serotonin. Excitation of the endings of the trigeminal nerve, which are widespread in the dura mater, is the initial stage in the formation and transmission of nociceptive informa- tion from the periphery to the CNS during migraine attacks [1, 2]. However, the neurochemical mechanisms of exci- tation of meningeal afferents remain poorly studied. The idea that local mast cells, present in large numbers in the meninges, have a large role in this process has become pop- ular in recent years [3–6]. Serotonin, along with histamine, accumulates in men- ingeal mast cells and is released as a result of the develop- ment of the pathological process [7]. Our recent research has identified that serotonin has a powerful pronociceptive action on trigeminal nerve terminals in rats and mice, medi- ated mainly via ionotropic 5-HT 3 receptors [4, 6]. However, the role of histamine in forming nociceptive signals in men- ingeal afferents remains poorly studied. Histamine is a classical neurotransmitter of the mono- amines group and is one of the best-known endogenous me- diators of pain and itch [8]. Histamine mediates biological effects by binding with four subtypes of metabotropic re- ceptor (H1–H4) [9, 10]. Binding activates intracellular mes- senger systems, including release of intracellular calcium or increases in cAMP levels [11]. Studies of the mechanisms of itch have shown that activation of H1 histamine receptors in nociceptive neurons leads to activation of TRPV1 recep- 1 Kazan Federal University, Kazan, Russia; e-mail: girashid13@gmail.com. 2 University of Eastern Finland, Kuopio, Finland. DOI 10.1007/s11055-020-00983-2