The pain field has had an ongoing need to develop better ways of assessing pain in animals, especially assays of """"""""spontaneous"""""""" or ongoing pain as opposed to tactile or thermal hypersensitivity. The headache field in particular for many years suffered from the severe limitation of having no behavioral assay. Current evidence now supports the idea that migraine and other headaches result from the activation of the sensory nerves that end in the meninges. Consequently, experimentally induced activation of these meningeal nerve endings has been used to investigate headache mechanisms. A major breakthrough was the demonstration that chemical meningeal (dural) stimulation induced facial allodynia in awake rats, providing for the first time a behavioral model of headache in animals. We now propose to pursue what we believe is a further breakthrough for the study of headache: a new observation of a change in """"""""spontaneous"""""""" behavior following chemical stimulation of the dura in rats. The core finding is a suppression of the normal exploratory behavior, and a concomitant increase in the amount of """"""""resting'behavior or quiet wakefulness. This may be considered an example of the more general phenomenon of suppression of an innate behavior/locomotor activity, which has been used as an approach for assessing spontaneous pain. The dural stimulus also induced a brief initial period of ipsilateral facial """"""""grooming"""""""" or rubbing that was done primarily with the hindpaw rather than the forepaw. Critically, these behavioral changes were partially blocked by triptan pre-treatment. We now propose to pursue these findings by characterizing this model in more detail in the rat, and by then using the same methods to also establish this model in mice. Experiments in the rat will: 1) evaluate the dose-response curve for this model, in order to find the lowest concentration of applied inflammatory mediators that is sufficient for producing a robust behavioral response, 2) measure CSF levels of the durally applied agents to investigate the amount of diffusion through the dura, and 3) pursue preliminary findings of changes in the EEG spectrum, consisting of an increase in theta activity, correlated with the bouts of increased """"""""resting"""""""" of quiet wakefulness, in the rats that received the dural stimulus. Studies in mice will compare different strains for both their nociceptive response and triptan sensitivity, and determine whether the order of high- vs low-responding strains differs from that found previously for other pain models. This will open an avenue for future studies into identifying genetic determinants of the response to dural stimulation and triptan sensitivity. Besides the significance of having a potential correlate of """"""""spontaneous"""""""" pain as opposed to stimulus-evoked hypersensitivity, this model also has the advantage that it avoids the necessity for applying von Frey testing, which is especially difficult in the mouse. Complementary studies will be carried out to examine anatomical markers of neural activation (fos and pERK) to correlate activation in superficial or deep dorsal horn laminae, as well as other central regions, with the magnitude of the behavioral response.

Public Health Relevance

Testing of behavioral responses of animals to noxious or painful stimuli is an essential starting point for research into mechanisms and treatment for pain and headache;however, current behavioral tests have relied primarily on testing of motor responses to noxious stimuli, such as reflex withdrawals, which can reveal conditions of hypersensitivity, but are not useful for studying conditions of spontaneous or ongoing pain. The present study will pursue a finding that represents a potential breakthrough for the study of headache, in that it provides for the first time a behavioral assay of assay of ongoing headache pain in animals. The development and use of this assay will open up an entirely new avenue of research for the identification of genetic and molecular mechanisms of headache.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Porter, Linda L
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Beth Israel Deaconess Medical Center
United States
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Zhao, Jun; Bree, Dara; Harrington, Michael G et al. (2017) Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine. Cephalalgia 37:1017-1025