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Control of Opioid Receptor Signaling and Pharmacological Tolerance through Endosomal Recycling and Retromer

Award Number: R01DA061885
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Control of Opioid Receptor Signaling and Pharmacological Tolerance through Endosomal Recycling and Retromer - Project Summary Opioids play a frontline role in acute pain management in the clinical setting. Prolonged use of opioids causes multiple adaptations including tolerance—a phenomenon in which increasing opioid dosage is required to maintain drug efficacy. The pharmacological component of opioid tolerance is largely driven on the cellular level and is the result of cellular protein networks terminating the activity of the mu opioid receptor (µOR). A critical step in this regulatory process is membrane trafficking. High efficacy opioids cause the µOR to rapidly traffic from the cell surface to internal cellular structures called endosomes. At endosomes, the µOR is either sorted back to the cell surface for continued activity (resensitization) or sent to the lysosome for destruction (downregulation). A long-standing model is that downregulation can drive pharmacological opioid tolerance through proteolysis of opioid receptors outpacing new receptor synthesis. One challenge in testing this model is that we don’t know the identity of key cellular protein networks regulating mu opioid receptor trafficking at endosomes. Here we leverage our recently developed proteomic and genomic methods for identifying cellular proteins which regulate opioid receptors. In Aim 1 we focus on the trafficking of the µOR at endosomes and, using biochemical and cellular techniques, test the hypothesis that the endosomal Retromer complex rescues mu opioid receptor from lysosomal degradation in a process called recycling. We will use functional genomics to identify potential druggable targets—kinases and ubiquitin-ligases—that regulate µOR through endosomes, and test the related hypothesis that opioid-induced downregulation of the µOR can be blocked by engineered “super-recycling” variants of the receptor. In Aim 2 we test the hypothesis that endosomal recycling and the endosomal Retromer complex controls three different phases of µOR signaling: endosomal signaling, resensitization, and the development of pharmacological opioid tolerance at the cellular level. Together, these studies seek to define a critical regulatory process controlling µOR function and identify cellular proteins which could be targeted to control the development pharmacological opioid 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: 2025 ( Subtotal = $453,062 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Drug Use and Addiction Research Programs	000	1	8/25/2025	NEW	$453,062
														Subtotal = $453,062

Grand Total All Awards = $453,062

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Control of Opioid Receptor Signaling and Pharmacological Tolerance through Endosomal Recycling and Retromer

Award Number: R01DA061885

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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