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Intracellular signaling mechanisms underlying opioid modulation of pain

Award Number: F30DA057838
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Intracellular signaling mechanisms underlying opioid modulation of pain - PROJECT SUMMARY Opioid use disorder is a public health crisis that stems from the highly addictive nature and potent analgesic properties of opioids. Opioids modulate circuitry involved in analgesia, pain-induced negative affect, motivation, reward, and addiction. They act on G-protein coupled opioid receptors, inducing multiple intracellular signaling pathways. Of these, the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) pathway is known to be a key mechanism in analgesia, pain-related aversion, and opioid- induced hyperalgesia. Most studies examining PKA signaling in response to opioids or pain are limited by in vitro or ex vivo approaches that cannot simultaneously consider cell-type specific PKA signaling, complex circuit-level regulation, and effects of behavior on PKA dynamics. As a result, it remains unclear exactly where and when PKA is modulated in response to opioids; nor is it clear what the functional effects of these spatiotemporal PKA dynamics are on analgesia. Understanding the functional significance of opioid-induced intracellular signaling and how this signaling differs in unique cell types and brain regions will allow us to better comprehend how opioids differentially effect pain and addiction circuitry. The goals of this proposal are as follows: First, I will define the temporal dynamics of mu opioid-induced PKA signaling within the mediodorsal thalamus (MD) to anterior cingulate cortex (ACC) circuitry. This circuitry highly expresses mu opioid receptors and integrates sensory and affective pain. Then, I will determine whether there is a causal relationship between these PKA dynamics and pain relief. Finally, I will examine the cell-type specificity of these PKA dynamics. My central hypothesis is that PKA dynamics will depend on the duration of opioid exposure and will determine the extent of pain response, with specific cell types acting as key sites of PKA modulation. This hypothesis will be tested using a novel genetically encoded sensor designed for in vivo imaging of PKA activity in behaving mice. To examine regional differences in temporal PKA dynamics in response to acute and chronic opioid exposure, PKA will be imaged before, during, and after opioid administration in the MD and ACC. Imaging will be paired with pain assays to assess analgesia and hyperalgesia. To test the necessity and sufficiency of PKA dynamics in pain relief, PKA activity will be modulated by either a genetically encoded PKA inhibitor or photoactivatable adenylyl cyclase while conducting behavioral assays of pain. Finally, to examine the cell-specificity of PKA dynamics, sensor expression will be isolated to each cell type of interest in a Cre-dependent manner, and peptide agonists and antagonists of mu opioid receptors will be locally infused during PKA imaging. This study will define how PKA signaling in specific components of the MD to ACC circuitry both responds to opioids and mediates pain relief. Achieving these goals will provide insight into how intracellular signaling is spatiotemporally regulated by opioids and facilitates analgesia.


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: 2025 ( Subtotal = $57,538 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	001	3	7/22/2025	NON-COMPETING CONTINUATION	$564
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	000	3	3/17/2025	NON-COMPETING CONTINUATION	$56,974
														Subtotal = $57,538

Issue Date FY: 2024 ( Subtotal = $56,974 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	000	2	1/30/2024	NON-COMPETING CONTINUATION	$55,194
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	001	2	5/1/2024	NON-COMPETING CONTINUATION	$1,780
														Subtotal = $56,974

Issue Date FY: 2023 ( Subtotal = $55,194 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	001	1	2/14/2023	NEW	$0
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	000	1	2/14/2023	NEW	$55,194
														Subtotal = $55,194

Grand Total All Awards = $169,706

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Intracellular signaling mechanisms underlying opioid modulation of pain

Award Number: F30DA057838

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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