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Signaling Mechanisms of Opioid-Induced Hyperalgesia and Tolerance

Award Number: R01DA041711
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Signaling Mechanisms of Opioid-Induced Hyperalgesia and Tolerance - Signaling Mechanisms of Opioid-induced Hyperalgesia and Tolerance Project Summary The major objective of this project is to identify key signaling mechanisms responsible for the development of opioid-induced hyperalgesia and analgesic tolerance (OHT). Opioid drugs remain indispensable for treating severe pain caused by surgery, trauma, and cancer. However, acute and repeated administration of μ-opioid receptor (MOR) agonists often cause OHT, the major obstacle to adequate pain relief with opioids. OHT can also lead to unsafe opioid dose escalation, resulting in dependence, addiction, and even overdose death. Opioid signaling is complex and has been studied mostly in vitro, but the functional significance and relevance of various opioid signaling components to OHT are poorly understood. N-methyl-D-aspartate receptors (NMDARs) are a clinically validated target for treating OHT, and extracellular signal-regulated kinase (ERK) is stimulated by MOR activation and is involved in opioid-induced NMDAR hyperactivity at the spinal cord level and in OHT. At present, little is known about the upstream signaling mechanism leading to stimulation of ERK at the spinal cord level during OHT. Although BRAF, a serine/threonine-specific protein kinase, is a crucial upstream signal for ERK activation, its role in OHT has not been recognized previously. In our preliminary studies, we found that repeated treatment with opioids increased BRAF activity in the spinal cord. Furthermore, BRAF inhibition or knockdown at the spinal cord level substantially attenuated OHT and rescued the synaptic trafficking and expression of MORs and NMDARs in the spinal cord altered by opioid treatment. These initial findings suggest that BRAF- dependent signaling plays a key role in the control of synaptic MOR and NMDAR plasticity in the development of OHT. Therefore, in this competing renewal application, we will test the overall hypothesis that repeated treatment with opioids, through the BRAF-mediated signaling axis, induces (1) analgesic tolerance by inhibiting expression and activity of MORs at primary afferent central terminals and (2) hyperalgesia by promoting trafficking and activity of NMDARs at primary afferent terminals synapsing with spinal cord excitatory neurons. To test this hypothesis, we will use a multidisciplinary approach, including protein biochemistry, electrophysiological recordings in spinal cord slices, and targeted gene knockout and knockin. Our proposed studies are expected to advance our understanding of the fundamental signaling mechanisms highly relevant to the development of OHT. Our project also has important clinical implications and could lead to new strategies (e.g., using FDA-approved BRAF inhibitors) for improving opioid analgesic efficacy in patients with severe pain.


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: 2026 ( Subtotal = $447,865 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	9	4/28/2026	NON-COMPETING CONTINUATION	$447,865
														Subtotal = $447,865

Issue Date FY: 2025 ( Subtotal = $447,865 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	8	4/18/2025	NON-COMPETING CONTINUATION	$447,865
														Subtotal = $447,865

Issue Date FY: 2024 ( Subtotal = $447,865 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	7	4/22/2024	NON-COMPETING CONTINUATION	$447,865
2024	2020	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	001	4	4/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $447,865

Issue Date FY: 2023 ( Subtotal = $447,865 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	6	5/19/2023	NON-COMPETING CONTINUATION	$447,865
														Subtotal = $447,865

Issue Date FY: 2022 ( Subtotal = $447,865 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	002	5	7/27/2022	COMPETING CONTINUATION	$447,865
2022	2020	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	001	4	7/22/2022	NON-COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	4	10/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $447,865

Issue Date FY: 2020 ( Subtotal = $402,312 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	001	4	2/7/2020	NON-COMPETING CONTINUATION	$40,232
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	4	12/3/2019	NON-COMPETING CONTINUATION	$362,080
														Subtotal = $402,312

Issue Date FY: 2019 ( Subtotal = $402,312 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	3	11/15/2018	NON-COMPETING CONTINUATION	$402,312
														Subtotal = $402,312

Issue Date FY: 2018 ( Subtotal = $402,312 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	2	11/15/2017	NON-COMPETING CONTINUATION	$362,080
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	001	2	4/26/2018	NON-COMPETING CONTINUATION	$40,232
														Subtotal = $402,312

Issue Date FY: 2017 ( Subtotal = $402,312 )
2017	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	1	1/26/2017	NEW	$402,312
														Subtotal = $402,312

Grand Total All Awards = $3,848,573

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Signaling Mechanisms of Opioid-Induced Hyperalgesia and Tolerance

Award Number: R01DA041711

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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