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Coupling activation of primary sensory neurons as a novel plasticity mechanism for chronic pain

Award Number: R01DE026677
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Coupling activation of primary sensory neurons as a novel plasticity mechanism for chronic pain - Chronic pain is affecting over 100 millions of U.S. adults with its debilitating medical problems, inadequate treatment, and severe economic burdens (over $600 billion). This is due to limited efficacy or intolerable side effects of available analgesic options. In order to better serve chronic pain patients, it is better to have clearer understanding of how chronic pain is generated. We don’t know exactly how innocuous stimuli (i.e. normal input to Aβ-fiber activation) become painful, leading to chronic pain after injury. And it remains unclear how the encoding of mechanosensory information to brain area is conveyed after it is sensitized at the level of primary sensory neuron and spinal cord. Although the mechanisms of hyperexcitability of individual DRG neurons have been extensively studied, how DRG neurons function at a populational level as an ensemble under physiological and pathological conditions is unclear due to the lack of suitable tools and techniques. Here, we developed an imaging technique that allowed us to simultaneously monitor the activation of >1,600 neurons/DRG in response to mechanical stimulation applied to the skin in live mice. And we now acquired and obtained mouse genetic tools that allow visualization of all four major Low Threshold Mechanoreceptor (LTMR) subtypes; Aβ, SA-LTMRs, Aβ, RA-LTMRs, Aδ-LTMRs, and C-LTMRs. Specific labeling of distinct sensory neuron subtypes provide an unprecedented opportunity to determine whether the activity of each subtype is altered during chronic pain after nerve injury. Using this powerful techniques and tools, we discovered a striking neuronal coupling phenomenon as a novel pain mechanism that adjacent neurons activate together following inflammation or nerve injury, although this rarely happens in naïve animals. This is the first demonstration that coupling phenomenon of primary sensory neurons after nerve injury contributes to new mechanisms underlying chronic pain conditions. This coupling activation occurs among various sizes of neurons including small-diameter nociceptors and large-diameter low-threshold mechanoreceptors. Combining the imaging technique with pharmacological and genetic approaches, we found that the coupling is, in part, mediated by an injury-induced upregulation of gap junction in satellite glial cells surrounding DRG neurons. Blocking gap junctions significantly attenuated neuronal coupling in the DRG and also reduced mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and by “hijacking” neighboring neurons through gap junction it contributes to pain hypersensitivity. Our studies suggest a new strategy to alleviate neuropathic pain by inhibiting gap junction connection between DRG neurons.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$15,692 )
2024	2021	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	6	10/24/2023	NON-COMPETING CONTINUATION	-$15,692
														Subtotal = -$15,692

Issue Date FY: 2022 ( Subtotal = $61 )
2022	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	000	2	9/26/2022	NON-COMPETING CONTINUATION	$61
														Subtotal = $61

Issue Date FY: 2021 ( Subtotal = $366,542 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	001	6	2/19/2021	NON-COMPETING CONTINUATION	$36,656
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	6	12/22/2020	NON-COMPETING CONTINUATION	$329,886
														Subtotal = $366,542

Issue Date FY: 2020 ( Subtotal = $365,750 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	5	12/31/2019	NON-COMPETING CONTINUATION	$329,175
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	001	5	2/18/2020	NON-COMPETING CONTINUATION	$36,575
2020	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	003	4	4/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$57,910
2020	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	002	2	4/5/2020	NON-COMPETING CONTINUATION	-$57,910
														Subtotal = $365,750

Issue Date FY: 2019 ( Subtotal = $365,750 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	002	4	8/30/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$365,750
2019	2019	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	000	3	12/12/2018	NON-COMPETING CONTINUATION	$368,125
2019	2019	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	001	3	8/29/2019	NON-COMPETING CONTINUATION	-$368,125
														Subtotal = $365,750

Issue Date FY: 2018 ( Subtotal = $368,125 )
2018	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	001	2	4/20/2018	NON-COMPETING CONTINUATION	$36,813
2018	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	000	2	12/22/2017	NON-COMPETING CONTINUATION	$331,312
														Subtotal = $368,125

Issue Date FY: 2017 ( Subtotal = $368,125 )
2017	2017	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	000	1	12/6/2016	NEW	$387,500
2017	2017	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Oral Diseases and Disorders Research	001	1	2/27/2017	NEW	-$19,375
														Subtotal = $368,125

Grand Total All Awards = $1,818,661

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Coupling activation of primary sensory neurons as a novel plasticity mechanism for chronic pain

Award Number: R01DE026677

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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