Abstract
BackgroundClinical observations suggest that hyperinsulinemia and insulin resistance can be associated with migraine headache. In the present study we examined the effect of insulin on transient receptor potential vanilloid 1 (TRPV1) receptor-dependent meningeal nociceptor functions in rats.MethodsThe effects of insulin on the TRPV1 receptor stimulation-induced release of calcitonin gene related peptide (CGRP) from trigeminal afferents and changes in meningeal blood flow were studied. Colocalization of the insulin receptor, the TRPV1 receptor and CGRP was also analyzed in trigeminal ganglion neurons.ResultsInsulin induced release of CGRP from meningeal afferents and consequent increases in dural blood flow through the activation of TRPV1 receptors of trigeminal afferents. Insulin sensitized both neural and vascular TRPV1 receptors making them more susceptible to the receptor agonist capsaicin. Immunohistochemistry revealed colocalization of the insulin receptor with the TRPV1 receptor and CGRP in a significant proportion of trigeminal ganglion neurons.ConclusionsInsulin may activate or sensitize meningeal nociceptors that may lead to enhanced headache susceptibility in persons with increased plasma insulin concentration.
Highlights
Clinical observations suggest that hyperinsulinemia and insulin resistance can be associated with migraine headache
Insulin releases calcitonin gene-related peptide (CGRP) from meningeal afferents by sensitizing transient receptor potential vanilloid 1 (TRPV1) receptors Basal release of CGRP measured in ex vivo dura mater preparations of control rats ranged between 2.98 ± 0.24 and 3.66 ± 0.31 pmol/l in different series of experiments that was statistically not different among experimental groups (p > 0.1)
In an in vivo rat dura mater preparation, we demonstrated earlier that application of the TRPV1 receptor agonist capsaicin to the exposed dura mater exerts a dual function; release of CGRP from trigeminal afferents increases meningeal blood flow, while capsaicin acting on vascular TRPV1 receptors constricts smooth muscle cells reducing meningeal blood flow by increased intracellular calcium concentration [12]
Summary
Clinical observations suggest that hyperinsulinemia and insulin resistance can be associated with migraine headache. In the present study we examined the effect of insulin on transient receptor potential vanilloid 1 (TRPV1) receptor-dependent meningeal nociceptor functions in rats. Hyperinsulinemia and insulin resistance have been associated with various pathophysiological conditions. Clinical studies suggest relationship between increased plasma insulin concentration and cardiovascular disorders such as hypertension, atherosclerosis and stroke [4]. Chronic migraine has a well-documented association with insulin resistance and metabolic syndrome [5, 6]. Relationship between enhanced insulin effect and migraine headache is further supported by the observation that hypoglycemia is a precipitating factor of Currently accepted hypothesis of migraine pathophysiology ascribes a significant role to activation and/or sensitization of trigeminal nociceptors innervating the meninges [9, 10]. Activation of trigeminal chemosensitive afferents results in the release of vasoactive neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P from their peripheral terminals which increase meningeal blood flow, degranulate mast cells and generate positive feedback reactions that may augment the initial
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