Nitroglycerin increases serotonin transporter expression in rat spinal cord but anandamide modulated this effect

Abstract

serotonin transporter expression in rat spinal cord but anandamide modulated this effect.Journal of Chemical Neuroanatomy http://dx.doi.org/10. 1016/j.jchemneu.2017.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Migraine is one of the most prevalent neurological diseases, which affects 16% of the total population. The exact pathomechanism of this disorder is still not well understood, but it seems that serotonin and its transporter has a crucial role in the pathogenesis.One of the animal models of migraine is the systemic administration of nitroglycerin (NTG), a nitric oxide (NO) donor. NO can initiate a central sensitization process in the trigeminal system, which is also present in migraineurs.Recent studies showed that the endocannabinoid system has a modulatory role on the trigeminal activation and sensitization.Our aim was to investigate the effect of an endogenous cannabinoid, anandamide (AEA) on the NTG-induced changes on serotonin transporter (5-HTT) expression in the upper cervical spinal cord (C1-C2) of the rat, where most of the trigeminal nociceptive afferents convey.The animals were divided into four groups. Rats in the first group, called placebo, received only the vehicle solution as treatment. In the second group, they were treated with an intraperitoneal (i.p.) injection of NTG (10mg/kg). Rats in the third and fourth groups received i.p. AEA (2x5mg/kg) half hour before and one hour after the placebo or NTG treatment. Four hours after placebo/NTG injection, the animals were perfused and the cervical spinal cords were removed for immunohistochemistry and Western blotting.Our results show that both NTG and AEA alone are able to increase 5-HTT expression in the C1-C2 segments. Combination of NTG and AEA has an opposing effect on this marker, nullifying the effects of non-combined administration, probably by negative feedback mechanisms.

Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks

“…This finding was unexpected, given preclinical data showing that exogenous administration of AEA prevented NTG-induced activation and sensitization of the trigeminal system. 29,30 A possible explanation for these apparently contrasting findings is that endocannabinoids may modulate migraine-related mechanisms upstream of NTG-induced effects, and not vice versa.…”

“…Considering their physiological analgesic and antiinflammatory functions, PEA and AEA may have positive effects on migraine attack recurrence and on sensitization processes. 29,30,35 Central sensitization is a hallmark of migraine, and it can be recorded at spinal level through evaluation of the nociceptive withdrawal reflex (NWR). 10,38 Nitroglycerin-induced migraine is also a validated human experimental model of the disease 5,16 that mimics several of its components besides headache: premonitory symptoms, allodynia, activation of specific brainstem circuitry, and central sensitization.…”

Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research

“…Akerman et al reported that capsaicin-induced vasodilation is less after intravenous administration of anandamide (AEA); in addition, AEA significantly prevented CGRP- and NO-induced vasodilation in the dura [ 204 ]. In a previous study, Nagy-Grócz and colleagues observed that NTG and AEA alone or combined treatment of them affects 5-HTT expression, which points out a possible interaction between the serotonergic and endocannabinoid system on the NTG-induced trigeminal activation and sensitization phenomenon, which are essential during migraine attacks [ 205 ]. These results raise the possibility that the AEA has a CB1 receptor-mediated inhibitory effect on neurogenic vasodilation of trigeminal blood vessels.…”

Models of Trigeminal Activation: Is There an Animal Model of Migraine?

“…Furthermore, NTG has also been shown to influence nNOS [76], CGRP [109], calcium/calmodulin-dependent protein kinase II alfa (CAMKIIα) [110], TRPV1 [111], nu-clear factor kappa B (NF-κB) [112], and cyclooxygenase-2 (COX-2) [113] levels in the trigeminal system of rats. In addition to this, 5-HT and its transporter levels increased in the trigeminal system of rats after NTG administration [109,114]. On the other hand, administration of NTG led to a notable reduction in the ambulation distance observed in rats [115], which can be compared to the loss of movement seen in migraineurs.…”