LIGHT and Lymphotoxin targeting for the treatment of chronic orofacial pain conditions

口腔面部慢性疼痛管理不善是阿片类药物过度使用和过量相关死亡的主要原因

Orofacial chronic pain mismanagement substantially contributes to opioid overuse, overdose related deaths and cardiovascular, renal and neurological complications at epidemic proportions. To combat this problem, it is necessary to elucidate a critical gap in knowledge by identifying and vigorously validating novel therapeutic targets controlling the development and maintenance of chronic orofacial pain. The current paradigm implies that orofacial conditions, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, could trigger maladaptation of the immune system and cell plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LTβ), members of the tumor necrosis factor superfamily, are critical components controlling a delicate balance between protective immunity and immunopathology during chronic inflammatory diseases. The objectives of this proposal are: first, to rigorously validate whether local blockade of LIGHT and LTβ signaling via LTβ receptor (LTβR) or Herpes Virus Entry Mediator (HVEM; TNFRSF14) prevent the development and/or inhibit maintenance of chronic pain in several models of TMJD and oral cancer; and second, to identify LIGHT and LTβ signaling-induced plasticity of immune, stromal and tumor cells in masseter muscle and tongue, as well as of sensory neurons in trigeminal ganglia (TG), leading to orofacial chronic pain. Based on the existing literature and our preliminary data, our central hypothesis is that targeting LIGHT and LTβ signaling will prevent the development and inhibit maintenance of chronic pain produced by TMJD and oral cancer via peripheral mechanisms involving plasticity of immune, stromal and tumor cells as well as sensory neurons. Our hypothesis will be tested by three relevant yet independent aims. Aim 1 validates whether local LIGHT and LTβ inhibition in masseter muscle prevents the development and blocks maintenance of chronic pain in TMJD models. Aim 2 defines contribution of LIGHT and LTβ to immune, stromal and neuronal cell plasticity during TMJD. Aim 3 determines whether LIGHT and LTβ signaling contribute to the development and maintenance of chronic pain in oral cancer models via regulation of cell plasticity in tongue. The proposed study is innovative because it validates novel targets to facilitate the development of orofacial chronic pain therapeutics; and proposes conceptually novel peripheral regulatory mechanisms involving LIGHT and LTβ signaling that control the development and maintenance of TMJD and oral cancer chronic pain. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain; and offers targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.