Insulin Enhances Nitroglycerin-Induced Hyperalgesia Through Insulin-Responsive Receptor Signalling Involving the Trigeminovascular System and Meningeal Mast Cells

Abstract

Migraine headache prevalence is lower in patients with diabetes, but the underlying mechanisms remains unclear. This study explored the influences of hyperglycemia, insulin and insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R)–related signalling on migraine-related mechanisms in in vivo and ex vivo rat models. In in vivo experiments, migraine-relevant responses were induced by systemic injection of nitroglycerin (NTG), whereas hyperglycemia was induced by streptozotocin (STZ). The effects of hyperglycemia, insulin and the dual IR/IGF-1R inhibitor BMS-754807 were investigated. In ex vivo experiments, the effects of insulin and BMS on basal and capsaicin-induced calcitonin gene-related peptide (CGRP) releases from migraine-associated tissues (peripheral meningeal afferents and trigeminal ganglion, and central brainstem trigeminal nucleus) were directly tested. Mechanical hyperalgesia was evaluated by von-Frey, CGRP and c-Fos levels by ELISA and meningeal mast cells by toluidine-blue staining. In in vivo NTG group, insulin further lowered the pain threshold and further enhanced CGRP and c-fos concentrations in trigeminal tissues and mast cell activation in the meninges. Hyperglycemia alone or in the NTG-treated group did not change these parameters. In ex vivo experiments, direct administration of insulin stimulated CGRP release in meningeal and trigeminal ganglion, but not trigeminal nucleus, tissues and further enhanced capsaicin-stimulated CGRP release, confirming the in vivo effects. The in vivo and ex vivo effects of insulin were reversed by BMS. Hyperglycemia did not modify the NTG-induced responses. However, insulin facilitates migraine-related responses by enhancing trigeminal CGRP signalling and meningeal mast cell activation through IR and/or IGF-1R-related signalling. Modulation of insulin-responsive IR/IGF-1R–related signalling within the trigeminovascular system may represent a potential target for future therapeutic strategies.