Tactile sensitivity of detecting gentle mechanical stimuli or touch is critically important in life but can be impaired to result in reduction/loss of tactile sensitivity (numbness) under pathological conditions. Numbness is the earliest and most common symptom of chemotherapy-induced peripheral neuropathy (CIPN) that negatively impacts quality of life in cancer patients, and it is a dose-limiting factor of chemotherapy. Numbness of CIPN is poorly treated and its underlying mechanism understudied. This lack of knowledge prevents development of effective management for numbness CIPN. ? A Merkel disc is a main type of tactile end organ located in touch sensitive spots throughout the body but most abundant at the human fingertips and whisker hair follicles of all non-primate mammals. A Merkel disc consists of a Merkel cell and an A?-afferent ending to form a synapse-like structure. We and others have recently discovered that tactile stimuli to Merkel discs are largely transduced in Merkel cells by Piezo2 channels, which drive most A?-afferent impulses and behavioral tactile responses. More recently, we have further identified that Merkel discs in whisker hair follicles are serotonergic synapses, and serotonin is released from Merkel cells in response to tactile stimuli to subsequently drive A?-afferent impulses and behavioral tactile responses. ? In this renewal application, our new focuses are to study how tactile sensitivity at Merkel discs is modulated and whether the tactile sensitivity can be impaired by chemotherapy drugs to account for the numbness aspect of CINP. ? We propose to use whisker hair follicle preparation to address these questions with 3 specific aims:
Aim 1) Elucidate mechanisms underlying the modulation of Merkel disc tactile sensitivity.
This Aim will focus on whether serotonin transporters play a key role in regulating Merkel disc serotonergic transmission and Merkel disc tactile sensitivity.
Aim 2 : Determine whether and how chemotherapy drugs impair Merkel disc tactile sensitivity.
This Aim will measure changes of serotonergic transmission and Merkel disc tactile sensitivity following chemotherapy drug treatment, and identify pre- and postsynaptic molecules at Merkel discs that are targeted by chemotherapy drugs to result in the impairment of Merkel disc tactile sensitivity.
Aim 3 : Determine whether targeting Merkel discs by chemotherapy drugs leads to impairment of behavioral tactile responses.
This Aim will determine whether chemotherapy drugs can impair whisker tactile behavioral responses via suppressing Merkel disc serotonergic transmission, and whether potentiation of Merkel disc serotonergic transmission by pharmacologically manipulating serotonin transporters can rescue the impaired whisker tactile behavioral responses. ? Completion of the 3 Aims will fill a scientific gap about tactile sensitivity of mammals, elucidate novel mechanisms underlying numbness aspect of CIPN, and identify potential therapeutic targets for rescuing impaired tactile sensitivity.

Public Health Relevance

The proposed research is relevant to public health because reduction/loss of tactile sensitivity (numbness) is the earliest and most common symptom of chemotherapy-induced peripheral neuropathy (CIPN) that negatively impacts quality of life in cancer patients and because CIPN is a dose-limiting factor of chemotherapy. Completion of this project will fill a scientific gap about tactile sensitivity and its modulation in mammals, elucidate novel mechanisms underlying the numbness aspect of CIPN, and identify potential therapeutic targets for rescuing impaired tactile sensitivity in CIPN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023090-08
Application #
9565988
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Vallejo, Yolanda F
Project Start
2013-09-01
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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
Viatchenko-Karpinski, Viacheslav; Gu, Jianguo G (2016) Mechanical sensitivity and electrophysiological properties of acutely dissociated dorsal root ganglion neurons of rats. Neurosci Lett 634:70-75

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