Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

Abstract

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.

Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats

“…The obvious problem with preclinical migraine research is that it does not mimic the spontaneous onset of migraine. Both pharmacological [23] and genetic [6] approaches have attempted to overcome this disconnect between preclinical models and the human situation. As before, these procedures have been limited because of the inability to continuously monitor migraine pain-related decreases in behavior.…”

Characterization of a mouse model of headache

“…Pretreatment of anti-migraine drugs sumatriptan and CGRP receptor antagonist effectively blocks IScap-induced behavior, suggesting that it may be mechanistically related to the ongoing headache during a migraine episode in humans. The effective dose of sumatriptan is higher than that required to inhibit facial allodynia in rat models of migraine [14, 44]. It is possible that larger dose of systemic sumatriptan is needed to block pain-related behavior in mice [5].…”

The Role of Adenosine Signaling in Headache: A Review

“…The second model, called the spontaneous trigeminal allodynia (STA) in rats, is currently the only model of primary trigeminal allodynia in animals [32]. Naturally born with this trait, no surgical procedure or pharmacological treatment is needed to produce an allodynic state that is confined to the trigeminal system.…”