{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:07:41Z","timestamp":1789992461714,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T00:00:00Z","timestamp":1510185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL134609"],"award-info":[{"award-number":["HL134609"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR\u2010059397"],"award-info":[{"award-number":["AR\u2010059397"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid\u2010sensing ion channel (ASIC) activation and reflexively increases mean arterial pressure; endomorphin release is also increased under inflammatory conditions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Intra\u2010arterial administration of lactic acid (to simulate exercising muscle and evoke a pressor reflex), endomorphin\u20102 and naloxone resulted in a significantly greater pressor response than lactic acid alone, while administration of APETx2 inhibited endomorphin's enhancing effect in both groups.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results suggest a novel role for endomorphins in modulating ASIC function to effect lactic acid\u2010mediated reflex increase in arterial pressure in patients with PAD.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid\u2010sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin\u20101 (E\u20101) and \u20102 (E\u20102), modulate ASIC currents and the lactic acid\u2010mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E\u20102 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72\u00a0h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin\u2010mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra\u2010arterial co\u2010administration of lactic acid and E\u20102 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E\u20102 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin\u20101. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid\u2010mediated reflex increase in arterial pressure that is MOR stimulation\u2010independent and APETx2\u2010sensitive.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp275058","type":"journal-article","created":{"date-parts":[[2017,10,17]],"date-time":"2017-10-17T03:52:50Z","timestamp":1508212370000},"page":"7167-7183","source":"Crossref","is-referenced-by-count":31,"title":["Endomorphins potentiate acid\u2010sensing ion channel currents and enhance the lactic acid\u2010mediated increase in arterial blood pressure: effects amplified in hindlimb ischaemia"],"prefix":"10.1113","volume":"595","author":[{"given":"Mohamed","family":"Farrag","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine Penn State College of Medicine  Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie 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