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Targeting Gut-Brain Axis Signaling to Treat Opioid Induced Hyperalgesia and Tolerance in Mice with Chronic Trigeminal Neuropathic Pain

Award Number: F31DE029686
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary/Abstract: Chronic pain is a significant health problem in the United States and in which there are limited treatment options available. Opioid drugs are commonly used in the treatment of chronic pain but carry with them serious side effects such as hyperalgesia (increased sensitivity to painful stimuli) and tolerance. These two side effects limit the effectiveness of opioids pain relieving ability and make the patient more susceptible to overdose. Previous research has shown opioids alter the gut microbiota. Downstream effects of an altered microbiota include increased gut inflammation, bile acid dysregulation, and change in vagal nerve and cortical activity. Preliminary data show that chronic opioid use alters short-chain fatty acid (SCFA) production in the gut and that modulating the gut microbiome through the ketogenic diet inhibits the maintenance of opioid induced hyperalgesia and tolerance. The direct link from the gut to the brain is through the vagal nerve. Recent work has shown that vagal nerve stimulation can modulate neuronal activity in the limbic system, including anterior cingulate cortex (ACC), a critical brain structure to be involved in chronic pain processing. Taken together, these findings lead to a central hypothesis that chronic opioid use causes microbiota changes in the gut which directly contributes to opioid induced hyperalgesia and tolerance by altering neuronal activity in the ACC through the vagal nerve, and that peripherally (ketogenic diet) or centrally (neuromodulation) targeted treatment modalities may be used to treat the opioid induced hyperalgesia and tolerance. Two aims are proposed to test this central hypothesis and to demonstrate that modulation of gut-brain axis by a dietary or neuromodulation approach can serve as potential therapeutic options. Aim 1: Establish the role of gut microbiota in the therapeutic effect of a special diet (ketogenic diet) on fentanyl induced hyperalgesia and tolerance under chronic pain by a) analyzing microbiota changes b) altering the microbiota with fecal microbiota transplantation or antibiotic administration c) measuring SCFAs and bile acids to detect the functional consequences of an altered microbiota due to chronic fentanyl treatment. Aim 2: Determine the effect of altered neuronal activity on fentanyl induced hyperalgesia and tolerance under chronic pain by a) measuring vagal nerve activity during chronic pain and opioid treatment b) examining the effect of altering vagal nerve activity on fentanyl induced hyperalgesia and tolerance c) investigating whether modulating ACC neuronal activity can treat fentanyl induced hyperalgesia and tolerance. Completion of this proposed project will provide new insight into how altered gut-brain signaling can lead to behavioral changes and how modulation of gut-brain axis can be used as a treatment strategy for fentanyl induced hyperalgesia and tolerance.


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: 2023 ( Subtotal = $37,928 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Oral Diseases and Disorders Research	000	4	5/18/2023	NON-COMPETING CONTINUATION	$37,928
														Subtotal = $37,928

Issue Date FY: 2022 ( Subtotal = $36,728 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	3	6/16/2022	NON-COMPETING CONTINUATION	$36,728
														Subtotal = $36,728

Issue Date FY: 2021 ( Subtotal = $35,765 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	2	6/14/2021	NON-COMPETING CONTINUATION	$35,765
														Subtotal = $35,765

Issue Date FY: 2020 ( Subtotal = $35,014 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	001	1	7/16/2020	NEW	$0
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	1	7/16/2020	NEW	$35,014
														Subtotal = $35,014

Grand Total All Awards = $145,435

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Targeting Gut-Brain Axis Signaling to Treat Opioid Induced Hyperalgesia and Tolerance in Mice with Chronic Trigeminal Neuropathic Pain

Award Number: F31DE029686

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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