Orofacial pain disorders encompass a wide range of conditions including trigeminal neuralgia, reflex sympathetic dystrophy (RSD) of the face, temporomandibular joint disorders, periodontal pain, burning mouth syndrome, dental surgical pain, head and neck cancer pain, pain due to oral infections, and other neuropathic and inflammatory pain conditions. One common symptom in many chronic orofacial pain conditions is cold allodynia/hyperalgesia, the excruciating painful sensation induced by cooling temperatures that would normally produce innocuous or mild painful cooling sensation. Unfortunately, the current clinical treatments are unsatisfactory for this chronic orofacial pain condition. This is largely due to the poor understanding of mechanisms for controlling cold sensitivity in trigeminal sensory system. We have recently accumulated evidence suggesting that cold sensitivity of nociceptive cold- sensing neurons may largely depend on low-threshold voltage-gated K+ channels (KLT), a subclass of voltage-gated K+ channels that are activated near resting membrane potentials. Furthermore, we found that pharmacologically potentiating KLT channels reversed orofacial cold allodynia/hyperalgesia. In this renewal application, the overall objectives are to study the role of KLT channels in controlling cold sensitivity of nociceptive cold-sensing trigeminal neurons under both physiological and trigeminal neuropathic conditions, and to explore therapeutic use of KLT channel potentiators for treating orofacial cold allodynia and hyperalgesia. Advanced neurological techniques including patch-clamp records and calcium imaging together with other approaches including immunostaining and novel animal models will be used in this project. By accomplishing our goal, we will have identified novel therapeutic targets for treating some intractable orofacial pain conditions.
Many clinical conditions including dental procedures, traumatic injury, tumors, and chemotherapy can result in chronic trigeminal nerve injury and degeneration. These often lead to the development of trigeminal neuropathic pain that manifests cold allodynia and hyperalgesia in orofacial regions. The trigeminal neuropathic pain constitutes a huge health problem because of its severity, special location, and resistance to conventional treatment. This project will use advanced neurobiological approaches and animal models to identify molecular and neuronal mechanisms underlying orofacial cold allodynia and hyperalgesia. The accomplishment of the Aims proposed in this project will lead to novel therapeutic targets for treating trigeminal neuropathic pain that manifests cold allodynia and hyperalgesia.
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