UBC Theses and Dissertations
A novel preclinical model of migraine : systemic monosodium glutamate administration Benbow, Tarique Vicario
Consumption of Monosodium Glutamate (MSG) in healthy people provokes headache, nausea and craniofacial tenderness that mimics that of an acute migraine attack in migraineurs. I hypothesize that systemic administration of MSG produces behavioural signs of headache, nausea and craniofacial tenderness through the activation of peripheral N-methyl-d-aspartate (NMDA) receptors in rats. The behavior of male and female Sprague Dawley rats was video recorded before and after intraperitoneal (i.p.) injections of either MSG (1-1000 mg/kg), nitroglycerin (GTN, 10 mg/kg) or normal saline. Behaviors (grimace score, head-flicks, rearing, head scratches, facial grooming, lying-on-belly, and temporalis muscle region mechanical withdrawal threshold (MT)) were evaluated. Facial cutaneous temperature of the nose and forehead was measured before and after i.p. injections via infrared thermography. Plasma glutamate and calcitonin-gene related peptide (CGRP) concentrations after administration of 1000 mg/kg MSG were measured in anesthetized rats. MSG induced headache- and nausea-like behaviors in a dose-related manner but had no effect on MT. MSG (1000 mg/kg) induced a significantly greater frequency of headache-like behavior in females, but a longer duration of nausea-like behavior in males. MSG produced a prolonged increase in plasma glutamate and CGRP concentrations. Co-administration of the median effective dose of MSG (350 mg/kg) with GTN (10 mg/kg) amplified headache-like behaviors, induced significant craniofacial sensitivity, and increased nausea-like behaviour. Co-administration of anti-migraine (sumatriptan and naproxen), anti-nausea (ondansetron and metoclopramide) drugs with MSG (1000 mg/kg) significantly attenuated MSG-induced headache and nausea-like behaviours respectively. Co-administration of the selective NMDA receptor antagonist 2R-amino-5-phosphonovaleric acid (APV 50 mg/kg), the non-NMDA receptor antagonist kynurenic acid (KYN 1 – 100 mg/kg) and the CGRP receptor antagonist (olcegepant 1 mg/kg), reduced headache-like behaviors evoked by MSG (1000 mg/kg). Only olcegepant when co-administered with MSG attenuated MSG-induced nausea-like behaviours. No alteration in motor function was observed by APV, KYN or olcegepant in rotarod experiments. My results suggest that systemic administration of MSG to rats induces behavioral correlates of headache and nausea that are mediated in part through peripheral NMDA receptor activation. Thus, systemic administration of MSG to rats may be used as a preclinical model for development and pre-clinical testing of new therapeutic targets in migraine.
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