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Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat
L F Ferrari1, J D Levine2, P G Green3
1Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States.
Neuroscience
|January 19, 2016
Summary
Nitroglycerin (GTN) causes delayed headache by activating mast cells, which stimulate endothelial cells. This pathway, involving ATP and P2X3 receptors, offers new migraine treatment targets.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Nitroglycerin (GTN) is known to induce headaches in migraineurs.
- The delayed onset of GTN-induced headache is not explained by GTN's rapid metabolism.
- Perivascular mast cell activation is a proposed mechanism for this delay.
Purpose of the Study:
- To investigate the role of mast cells and endothelial cells in the delayed hyperalgesia induced by GTN.
- To explore potential therapeutic targets for GTN-induced headaches and migraine.
Main Methods:
- Administered intradermal GTN to rats to induce hyperalgesia.
- Utilized sumatriptan, compound 48/80, octoxynol-9, and A-317491 to test mechanistic hypotheses.
- Measured mechanical hyperalgesia and assessed the effects of various pretreatments.
Main Results:
- GTN induced delayed mechanical hyperalgesia in rats, with a longer delay in females.
- Sumatriptan and chronic mast cell degranulation prevented GTN-induced hyperalgesia.
- GTN and mast cell-mediated hyperalgesia were dependent on endothelial cell function and P2X3 receptors.
Conclusions:
- Delayed-onset hyperalgesia from GTN is mediated by mast cell activation.
- Mast cells activate endothelial cells, leading to ATP release and stimulation of P2X3 receptors on perivascular nociceptors.
- Mast and endothelial cells represent potential targets for novel migraine therapies.
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