Episodic Dural Stimulation in Awake Rats: A Model for Recurrent Headache
Episodic Dural Stimulation in Awake Rats: A Model for Recurrent Headache
Objectives: To model, in rats, the development of chronic trigeminal nociceptive hypersensitivity seen in patients with recurrent headache.
Background: Pathophysiology studies suggest that patients with recurrent migraine headache experience repeated bouts of dural nociceptor activation. In some patients, the severity and frequency of headache attacks increase over time. Patients with recurrent headache are hypersensitive to nitric oxide donors, such as glyceryl trinitrate (GTN).
Current trigeminal pain models do not reflect the repeated episodic nature of dural nociceptor activation in patients with recurrent headache. Repeated nociceptor activation creates long-lasting changes in the periphery and brain due to activity-dependent neuronal plasticity. An animal model of repeated activation of dural nociceptors will facilitate the study of the physiological changes caused by repeated, episodic pain and the factors important for the transition of episodic to chronic migraine.
Methods: We induced dural inflammation by infusing an inflammatory soup (IS) through a cannula on the dura in awake behaving rats. This was repeated 3 times per week for up to 4 weeks. Periorbital pressure sensory testing was used to monitor the change in trigeminal sensitivity. Rats were challenged with GTN to test the hypothesis that many dural stimulations are required to model the hypersensitivity of migraine patients. Quantitative trigeminal sensory testing and microdialysis in the trigeminal nucleus caudalis (TNC) were used to measure GTN hypersensitivity.
Results: Multiple infusions of IS (>8), over weeks, induced a long-lasting decrease in periorbital pressure thresholds that lasted >3 weeks after the last infusion. In contrast, IS infusion in IS-naive rats and those that received 3 IS infusions produced only short-lasting decreases in periorbital pressure thresholds.
Rats that received more than 8 IS infusions showed a marked increase in their neurochemical and behavioral responses to GTN. In these rats, GTN induced a decrease in periorbital von Frey thresholds that lasted >5 hours. In contrast, in rats that received only 3 IS infusions, GTN caused a threshold decrease for 1.5 hour.
In vivo microdialysis in the TNC showed that GTN increased extracellular glutamate levels in rats with more than 8 IS infusions to 7.7 times the basal levels. In IS-naive rats and those that received only 3 IS infusions, the extracellular glutamate levels rose to only 1.7 and 1.9 times the basal level, respectively.
Conclusions: Repeated IS stimulation of the dura produces a chronic state of trigeminal hypersensitivity and potentiates the response to GTN. This hyperresponsiveness outlasts the last IS infusion and is the basis of our rat model of recurrent headache. This model can be used to study the changes in the brain and periphery induced by repeated trigeminovascular nociceptor activation and has the potential to elucidate the mechanisms for the transition of episodic to chronic headache.
This study describes a new model of recurrent headache in rats. Our model uses repeated inflammatory dural stimulation to mimic the repeated activation of dural afferents believed to occur in patients with recurrent migraine headache. After multiple inflammatory stimulations of the dura, there is an unique physiological state generated in the rats that is stable, and long outlasts the last stimulation. This state is characterized by sensory and physiological hyperresponsiveness of the trigeminal neurovascular system that significantly differs from the relatively short-lasting and smaller magnitude changes induced by a single acute stimulation of the dura.
The pain phase of migraine involves nociceptor activation due to either neurogenic inflammation or another, unknown, mechanism. According to this theory, patients experience repeated attacks of nociceptor activation on the dura over time, separated by pain-free periods. Current animal model of headache do not reflect the repeated trigeminovascular nociceptor activation in patients with recurrent headache. Repeated, episodic nociceptor activation creates long-lasting changes in the periphery and the brain and can increase the perception of pain in secondary or referred areas due to activity-dependent neuronal plasticity. An animal model of repeated activation of the dural nociceptors is needed to reveal new mechanisms of trigeminal pain chronification and the factors important for the transition of episodic to chronic headache.
Electrophysiology and microdialysis studies in the trigeminal nucleus caudalis (TNC) demonstrate that an acute chemical stimulation of the rat dura, using a mixture of inflammatory mediators, is a nociceptive stimulus that both activates and sensitizes dural C and Aδ nociceptors for hours. There are no published reports of the effects of repeated chemical dural stimulation on rat behavior and physiology.
The nitric oxide (NO) donor, glyceryl trinitrate (GTN), induces migraine-like headaches in patients with migraine. In healthy subjects, only a short-lasting headache is induced that resolves after the first hour. In migraine patients, the NO-induced headache lasts >5 hours and can even be associated with premonitory symptoms. Because very few healthy subjects experience migraine-like headache following GTN injection, it has been suggested that GTN can be used to diagnose migraine. Hypersensitivity to exogenous NO experienced by patients with recurrent headaches suggests that repeated episodes of headache pain sensitizes the brain to NO and vasodilation of the dural blood vessels. Although there is little experimental evidence, it is believed that increased neuronal excitability in the brain and periphery, due to prolonged or repeated nociceptive input, is important in the pathophysiology of chronic pain and recurrent headache.
Studies of GTN's effects in acute, one-time trigeminal pain models in rats show that it has little or no effect. One study showed that GTN did not induce c-FOS expression or cause the release of calcitonin gene-related peptide (CGRP) in an intact animal, but GTN facilitated the release of CGRP in response to capsaicin. Two studies showed that GTN potentiated sensory responses, but the effect of GTN alone was weak in one study and no different than control in another. A study using a hemisected skull showed that the NO donor NONOate caused an increase in CGRP release in a dose-dependent manner. These studies demonstrate that GTN facilitates sensory responses in rats, but the effect of GTN alone is minimal. We challenged rats that received many inflammatory stimulations of the dura with GTN and found that their response was much higher than rats that received only 3 stimulations. This demonstrates that many inflammatory stimulations of the dura are required to model the hyperresponsiveness of humans with recurrent headache to GTN.
The aim of this study was to demonstrate that repeated episodic activation of the trigeminovascular system leads to chronic trigeminal hypersensitivity that models the hypersensitivity of patients with recurrent headache. Our goal was to demonstrate, using sensory and physiological measures, that our model provides a system for the study of episodic and chronic headache disorders.
Abstract and Introduction
Abstract
Objectives: To model, in rats, the development of chronic trigeminal nociceptive hypersensitivity seen in patients with recurrent headache.
Background: Pathophysiology studies suggest that patients with recurrent migraine headache experience repeated bouts of dural nociceptor activation. In some patients, the severity and frequency of headache attacks increase over time. Patients with recurrent headache are hypersensitive to nitric oxide donors, such as glyceryl trinitrate (GTN).
Current trigeminal pain models do not reflect the repeated episodic nature of dural nociceptor activation in patients with recurrent headache. Repeated nociceptor activation creates long-lasting changes in the periphery and brain due to activity-dependent neuronal plasticity. An animal model of repeated activation of dural nociceptors will facilitate the study of the physiological changes caused by repeated, episodic pain and the factors important for the transition of episodic to chronic migraine.
Methods: We induced dural inflammation by infusing an inflammatory soup (IS) through a cannula on the dura in awake behaving rats. This was repeated 3 times per week for up to 4 weeks. Periorbital pressure sensory testing was used to monitor the change in trigeminal sensitivity. Rats were challenged with GTN to test the hypothesis that many dural stimulations are required to model the hypersensitivity of migraine patients. Quantitative trigeminal sensory testing and microdialysis in the trigeminal nucleus caudalis (TNC) were used to measure GTN hypersensitivity.
Results: Multiple infusions of IS (>8), over weeks, induced a long-lasting decrease in periorbital pressure thresholds that lasted >3 weeks after the last infusion. In contrast, IS infusion in IS-naive rats and those that received 3 IS infusions produced only short-lasting decreases in periorbital pressure thresholds.
Rats that received more than 8 IS infusions showed a marked increase in their neurochemical and behavioral responses to GTN. In these rats, GTN induced a decrease in periorbital von Frey thresholds that lasted >5 hours. In contrast, in rats that received only 3 IS infusions, GTN caused a threshold decrease for 1.5 hour.
In vivo microdialysis in the TNC showed that GTN increased extracellular glutamate levels in rats with more than 8 IS infusions to 7.7 times the basal levels. In IS-naive rats and those that received only 3 IS infusions, the extracellular glutamate levels rose to only 1.7 and 1.9 times the basal level, respectively.
Conclusions: Repeated IS stimulation of the dura produces a chronic state of trigeminal hypersensitivity and potentiates the response to GTN. This hyperresponsiveness outlasts the last IS infusion and is the basis of our rat model of recurrent headache. This model can be used to study the changes in the brain and periphery induced by repeated trigeminovascular nociceptor activation and has the potential to elucidate the mechanisms for the transition of episodic to chronic headache.
Introduction
This study describes a new model of recurrent headache in rats. Our model uses repeated inflammatory dural stimulation to mimic the repeated activation of dural afferents believed to occur in patients with recurrent migraine headache. After multiple inflammatory stimulations of the dura, there is an unique physiological state generated in the rats that is stable, and long outlasts the last stimulation. This state is characterized by sensory and physiological hyperresponsiveness of the trigeminal neurovascular system that significantly differs from the relatively short-lasting and smaller magnitude changes induced by a single acute stimulation of the dura.
The pain phase of migraine involves nociceptor activation due to either neurogenic inflammation or another, unknown, mechanism. According to this theory, patients experience repeated attacks of nociceptor activation on the dura over time, separated by pain-free periods. Current animal model of headache do not reflect the repeated trigeminovascular nociceptor activation in patients with recurrent headache. Repeated, episodic nociceptor activation creates long-lasting changes in the periphery and the brain and can increase the perception of pain in secondary or referred areas due to activity-dependent neuronal plasticity. An animal model of repeated activation of the dural nociceptors is needed to reveal new mechanisms of trigeminal pain chronification and the factors important for the transition of episodic to chronic headache.
Electrophysiology and microdialysis studies in the trigeminal nucleus caudalis (TNC) demonstrate that an acute chemical stimulation of the rat dura, using a mixture of inflammatory mediators, is a nociceptive stimulus that both activates and sensitizes dural C and Aδ nociceptors for hours. There are no published reports of the effects of repeated chemical dural stimulation on rat behavior and physiology.
The nitric oxide (NO) donor, glyceryl trinitrate (GTN), induces migraine-like headaches in patients with migraine. In healthy subjects, only a short-lasting headache is induced that resolves after the first hour. In migraine patients, the NO-induced headache lasts >5 hours and can even be associated with premonitory symptoms. Because very few healthy subjects experience migraine-like headache following GTN injection, it has been suggested that GTN can be used to diagnose migraine. Hypersensitivity to exogenous NO experienced by patients with recurrent headaches suggests that repeated episodes of headache pain sensitizes the brain to NO and vasodilation of the dural blood vessels. Although there is little experimental evidence, it is believed that increased neuronal excitability in the brain and periphery, due to prolonged or repeated nociceptive input, is important in the pathophysiology of chronic pain and recurrent headache.
Studies of GTN's effects in acute, one-time trigeminal pain models in rats show that it has little or no effect. One study showed that GTN did not induce c-FOS expression or cause the release of calcitonin gene-related peptide (CGRP) in an intact animal, but GTN facilitated the release of CGRP in response to capsaicin. Two studies showed that GTN potentiated sensory responses, but the effect of GTN alone was weak in one study and no different than control in another. A study using a hemisected skull showed that the NO donor NONOate caused an increase in CGRP release in a dose-dependent manner. These studies demonstrate that GTN facilitates sensory responses in rats, but the effect of GTN alone is minimal. We challenged rats that received many inflammatory stimulations of the dura with GTN and found that their response was much higher than rats that received only 3 stimulations. This demonstrates that many inflammatory stimulations of the dura are required to model the hyperresponsiveness of humans with recurrent headache to GTN.
The aim of this study was to demonstrate that repeated episodic activation of the trigeminovascular system leads to chronic trigeminal hypersensitivity that models the hypersensitivity of patients with recurrent headache. Our goal was to demonstrate, using sensory and physiological measures, that our model provides a system for the study of episodic and chronic headache disorders.
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