Effects of a High Omega-6 Diet on Orofacial Allodynia

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ABSTRACT Chronic orofacial pain is estimated to be experienced by up to 25% of the adult population, which greatly decreases quality of life. A common complaint of orofacial pain is from mechanical stimuli. Current treatments for various orofacial pain conditions are limited. Physicians recommend dietary interventions for management of disorders such as cardiovascular disease and diabetes, but less is known about how diet may alleviate pain. It is possible that diet may also contribute to chronic orofacial pain conditions, as omega-6 polyunsaturated fatty acids (PUFAs) such as linoleic acid (LA) and arachidonic acid (AA), are essential PUFAs that are regulated by dietary intake and known to be pronociceptive. Our data demonstrate that mice fed an 8-week high omega-6 diet (H6D) exhibit increased plasma membrane levels of LA and AA in dorsal root ganglia (DRG) and increased hindpaw sensitivity to mechanical stimuli. LA, AA, and their metabolites could be regulating nociception through activation of channels in primary afferent nociceptors. More specifically, LA and AA are cleaved from membranes by phospholipase A2 (PLA2) isozymes where they can be oxidized into biologically active metabolites, which can activate targets like transient receptor potential channels expressed on primary afferent nociceptors. Therefore, the release of omega-6 PUFAs from cellular membranes may play a key role in regulating nociceptor activities and pain. However, it is unknown whether a H6D is a pain risk factor in orofacial tissues innerved by trigeminal ganglia (TG) afferent neurons. Given the distinct molecular expression differences between TG and DRG neurons, studies on the role of H6D as a risk factor for orofacial pain must be conducted in the TG system. Our preliminary data demonstrates that mice fed a H6D for 8-weeks exhibit significantly increased orofacial responsiveness to mechanical stimuli filaments. There is a large gap in knowledge as to the mechanisms by which dietary intake of omega-6 lipids serves as a risk factor for orofacial pain. Based on recent studies and our preliminary data, we propose to test the central hypothesis that increased dietary omega-6 PUFAs sensitize trigeminal sensory neurons and increase nociceptive behaviors in preclinical models of inflammatory and neuropathic orofacial pain via neuronal phospholipase A2. To investigate the role of diet on orofacial pain, we will 1) examine the role of H6D in sensitization of sensory neurons, 2) determine if H6D is a pronociceptive risk factor in models of orofacial pain conditions, and 3) identify PLA2 isozymes mediated H6D- induced effects on mechanical nociceptive behaviors. The scientific significance is based on an innovative hypothesis and may lead to novel therapeutic interventions for orofacial pain conditions. Although dietary recommendations are made for many diseases, they represent a new approach for managing orofacial pain. These dietary interventions may offer considerable clinical translational applications with relatively low cost and adverse effects. Equally important, techniques and research experiences comprise an outstanding training vehicle for my future career as an academic clinician-scientist.