Thursday, November 21, 2024 11/21/2024

Opioid-induced potentiation of the exercise pressor reflex via acid-sensing ion channels (ASIC3) in health and simulated peripheral artery disease

Award Number: R01HL156513
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Chronic ischemia in muscle (skeletal or cardiac) leads to accumulation of lactic acid and other inflammatory metabolites with subsequent drop in interstitial pH. The ensuing tissue acidosis plays a major role in triggering claudication (walking-induced pain) and chest pain. The high-affinity and selective mu opioid receptor (MOR) agonists, endomorphins, are also released under ischemic and inflammatory conditions. Acid-sensing ion channels (ASIC) are key players in the perception of pH changes associated with tissue acidosis, inflammation and pain. ASIC are expressed highly in sensory (i.e. dorsal root ganglion, DRG) and central neurons and are voltage-insensitive, depolarizing cationic channels. Endomorphin-1 (E-1) and -2 (E-2) are tetrapeptides known to activate MOR and exert analgesic effects. However, our recent findings indicate that E- 1 and E-2 significantly potentiated the acid-induced ASIC3 currents in transfected fibroblast L-cells and in acutely isolated DRG neurons independent of MOR activation. The potentiation by both opioids was significantly greater in DRG neurons isolated from rats with ligated femoral arteries (peripheral artery disease model). Importantly, our in vivo data demonstrated that E-2 significantly enhanced the lactic acid-induced increase in mean arterial pressure in rats. The E-2-mediated enhancement was significantly attenuated by the ASIC3 blocker, APETx2, but was insensitive to naloxone. Our long-term goal is to understand the mechanisms by which endomorphins and clinically employed opiates (oxycodone, fentanyl, remifentanil) modulate ASIC3 currents, the interacting site on the channel, and how they regulate the exercise pressor reflex (EPR) which is evoked by muscle contraction. Our overall hypothesis is that chronic muscle ischemia—accompanied by an acidified and inflamed environment, and enhanced ASIC3 expression— elevates endomorphin release, leading to enhanced ASIC3 currents. The overall effect is hyperexcitability of primary afferents that produces an exaggerated EPR. This hypothesis will be tested using complementary in vitro and in vivo approaches. We will determine the biophysical and pharmacological effects of endomorphins and prescription opiates on heterologously expressed ASIC3 in L-cells. We will identify ASIC3 channel residues that functionally negate the actions of E-1 and E-2, but leave the basic physiology of the channel intact. We also will compare the opioid agonist pharmacological profiles on ASIC channel currents in DRG neurons from rats with “freely perfused” or “ligated” femoral arteries. We will examine the effects of E-1, E-2 and prescription opiates on the EPR evoked in both wild-type and ASIC3 knockout rats in which the femoral arteries are “freely perfused” or “ligated”. Overall, these experiments will provide novel information about how opioid peptides potentiate ASIC currents under ischemic conditions, thereby enhancing pressor responses to exercise and possibly worsening pain associated with chronic use of prescription opiates (i.e., opioid-induced hyperalgesia).


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 = $601,199 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	4	3/22/2024	NON-COMPETING CONTINUATION	$552,123
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	001	4	6/19/2024	NON-COMPETING CONTINUATION	$49,076
														Subtotal = $601,199

Issue Date FY: 2023 ( Subtotal = $613,470 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	3	3/27/2023	NON-COMPETING CONTINUATION	$613,470
														Subtotal = $613,470

Issue Date FY: 2022 ( Subtotal = $613,470 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	2	3/16/2022	NON-COMPETING CONTINUATION	$552,122
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	001	2	6/29/2022	NON-COMPETING CONTINUATION	$61,348
														Subtotal = $613,470

Issue Date FY: 2021 ( Subtotal = $613,470 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	1	4/20/2021	NEW	$552,124
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	001	1	6/23/2021	NEW	$61,346
														Subtotal = $613,470

Grand Total All Awards = $2,441,609

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Opioid-induced potentiation of the exercise pressor reflex via acid-sensing ion channels (ASIC3) in health and simulated peripheral artery disease

Award Number: R01HL156513

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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