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Anna Matynia, Sachin Parikh, Nurali Avliyakulov, Michael Haykinson, Michael B. Gorin; Genetic And Ocular Influences On Light Aversion In Mouse Models Of Photoallodynia. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4348.
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Photoallodynia, frequently called photophobia, is not a fear of light as suggested by the commonly used term but is the perception of discomfort or pain in the presence of normal light, and is a clinical problem of increasing concern and interest. The majority of mild traumatic brain injury patients and migraine patients, as well as many patients with corneal injury or cone dysfunction experience photoallodynia. We aim to understand the molecular, biochemical and neural mechanisms of photoallodynia using mouse models and light aversion as an endophenotype of photoallodynia.
We have developed a light aversion behavioral test and have assessed the contribution of specific retinal circuitry components using mutant mice. Tetravisc and atropine were used to investigate the role of extraocular nociception and pupil dilation on light aversion, respectively. Low dose morphine was used to generate a novel, acute, atraumatic model of severe light aversion. We performed proteomic analysis to identify protein modification changes in the retina and have commenced analysis of the neural circuitry mediating light aversion in this morphine-induced model of light aversion.
Previously, we showed that photoallodynia is not dependent on rod or cone input since mutants lacking functional cones (Gnat2-/-, n=6 and Cnga3-/-, n=7), rods (Gnat1-/-, n=10) show normal light aversion. Furthermore, mice lacking cones, or rods and cones also exhibit normal light aversion (H.reddta/dta, n=12, rd1/rd1, n=6) Atropine pupillary dilation shows a step-like increase in light aversion at ~250 lux, implicating recruitment of melanopsin-positive, intrinsically photosensitive retinal ganglion cells (ipRGCs). Mice lacking ipRRGCs show decreased light aversion under normal conditions and with atropine-dilated pupils (Opn4dta/dta, n=15 and 8, respectively). These mutants, and the mice lacking rods and cones show the same enhanced light sensitivity to low-dose morphine. We have determined the sensitivity thresholds for morphine dose and illumination level in this acute model and have used subunit specific opiate antagonists as well as µ opioid receptor deletion mice to confirm the role of the mu opiate receptor.
We have established that neither rod nor cone photoreceptors, either singly or together, are required for light aversive behavior. In contrast, ipRGCs appear to be critical for integration of light detection from both photoreceptors and melanopsin, and coordinate aversion behaviour via activation of the appropriate brain nuclei. A secondary bypass system is likely activated by sub-analgesic exogenous opiate agonists acting either locally on retinal neurons and/or within the central nervous system.
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