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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Wan, Jason
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University of Cincinnati
Schools of Medicine
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Viatchenko-Karpinski, Viacheslav; Ling, Jennifer; Gu, Jianguo G (2018) Down-regulation of Kv4.3 channels and a-type K+ currents in V2 trigeminal ganglion neurons of rats following oxaliplatin treatment. Mol Pain 14:1744806917750995
Viatchenko-Karpinski, Viacheslav; Ling, Jennifer; Gu, Jianguo G (2018) Characterization of temperature-sensitive leak K+ currents and expression of TRAAK, TREK-1, and TREK2 channels in dorsal root ganglion neurons of rats. Mol Brain 11:40
Ling, Jennifer; Erol, Ferhat; Gu, Jianguo G (2018) Role of KCNQ2 channels in orofacial cold sensitivity: KCNQ2 upregulation in trigeminal ganglion neurons after infraorbital nerve chronic constrictive injury. Neurosci Lett 664:84-90
Kanda, Hirosato; Gu, Jianguo G (2017) Membrane Mechanics of Primary Afferent Neurons in the Dorsal Root Ganglia of Rats. Biophys J 112:1654-1662
Kanda, Hirosato; Gu, Jianguo G (2017) Effects of cold temperatures on the excitability of rat trigeminal ganglion neurons that are not for cold sensing. J Neurochem 141:532-543
Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo et al. (2017) Serotonergic transmission at Merkel discs: modulation by exogenously applied chemical messengers and involvement of Ih currents. J Neurochem 141:565-576
Ling, Jennifer; Erol, Ferhat; Viatchenko-Karpinski, Viacheslav et al. (2017) Orofacial neuropathic pain induced by oxaliplatin: downregulation of KCNQ2 channels in V2 trigeminal ganglion neurons and treatment by the KCNQ2 channel potentiator retigabine. Mol Pain 13:1744806917724715
Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo et al. (2016) Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals. Proc Natl Acad Sci U S A 113:E5491-500
Ikeda, Ryo; Gu, Jianguo (2016) Electrophysiological property and chemical sensitivity of primary afferent neurons that innervate rat whisker hair follicles. Mol Pain 12:
Kanda, Hirosato; Clodfelder-Miller, Buffie J; Gu, Jianguo G et al. (2016) Electrophysiological properties of lumbosacral primary afferent neurons innervating urothelial and non-urothelial layers of mouse urinary bladder. Brain Res 1648:81-89

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