Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
01 Nov 2023
01 Nov 2023
Historique:
received:
25
07
2022
accepted:
25
04
2023
medline:
30
10
2023
pubmed:
16
6
2023
entrez:
16
6
2023
Statut:
ppublish
Résumé
Targeting the acidified inflammatory microenvironment with pH-sensitive opioids is a novel approach for managing visceral pain while mitigating side effects. The analgesic efficacy of pH-dependent opioids has not been studied during the evolution of inflammation, where fluctuating tissue pH and repeated therapeutic dosing could influence analgesia and side effects. Whether pH-dependent opioids can inhibit human nociceptors during extracellular acidification is unexplored. We studied the analgesic efficacy and side-effect profile of a pH-sensitive fentanyl analog, (±)- N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide (NFEPP), during the evolution of colitis induced in mice with dextran sulphate sodium. Colitis was characterized by granulocyte infiltration, histological damage, and acidification of the mucosa and submucosa at sites of immune cell infiltration. Changes in nociception were determined by measuring visceromotor responses to noxious colorectal distension in conscious mice. Repeated doses of NFEPP inhibited nociception throughout the course of disease, with maximal efficacy at the peak of inflammation. Fentanyl was antinociceptive regardless of the stage of inflammation. Fentanyl inhibited gastrointestinal transit, blocked defaecation, and induced hypoxemia, whereas NFEPP had no such side effects. In proof-of-principle experiments, NFEPP inhibited mechanically provoked activation of human colonic nociceptors under acidic conditions mimicking the inflamed state. Thus, NFEPP provides analgesia throughout the evolution of colitis with maximal activity at peak inflammation. The actions of NFEPP are restricted to acidified layers of the colon, without common side effects in normal tissues. N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide could provide safe and effective analgesia during acute colitis, such as flares of ulcerative colitis.
Identifiants
pubmed: 37326658
doi: 10.1097/j.pain.0000000000002956
pii: 00006396-990000000-00327
doi:
Substances chimiques
propionamide
QK07G0HP47
Analgesics, Opioid
0
Analgesics
0
Fentanyl
UF599785JZ
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2501-2515Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE029951
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102722
Pays : United States
Informations de copyright
Copyright © 2023 International Association for the Study of Pain.
Références
Adochite RC, Moshnikova A, Carlin SD, Guerrieri RA, Andreev OA, Lewis JS, Reshetnyak YK. Targeting breast tumors with pH (Low) insertion peptides. Mol Pharmaceutics 2014;11:2896–905.
Algera MH, Olofsen E, Moss L, Dobbins RL, Niesters M, van Velzen M, Groeneveld GJ, Heuberger J, Laffont CM, Dahan A. Tolerance to opioid-induced respiratory depression in chronic high-dose opioid users: a model-based comparison with opioid-Naïve individuals. Clin Pharmacol Ther 2021;109:637–45.
Andreev OA, Dupuy AD, Segala M, Sandugu S, Serra DA, Chichester CO, Engelman DM, Reshetnyak YK. Mechanism and uses of a membrane peptide that targets tumors and other acidic tissues in vivo. Proc Natl Acad Sci U S A 2007;104:7893–8.
Baamonde A, Menéndez L, González-Rodríguez S, Lastra A, Seitz V, Stein C, Machelska H. A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors. Sci Rep 2020;10:18599.
Bábíčková J, Tóthová Ľ, Lengyelová E, Bartoňová A, Hodosy J, Gardlík R, Celec P. Sex differences in experimentally induced colitis in mice: a role for estrogens. Inflammation 2015;38:1996–2006.
Bagnol D, Mansour A, Akil H, Watson SJ. Cellular localization and distribution of the cloned mu and kappa opioid receptors in rat gastrointestinal tract. Neuroscience 1997;81:579–91.
Bateman JT, Saunders SE, Levitt ES. Understanding and countering opioid-induced respiratory depression. Br J Pharmacol 2021;180:813–28.
Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol 2014;104:15.25.1–14.
Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and exogenous opioids in pain. Annu Rev Neurosci 2018;41:453–73.
Del Vecchio G, Labuz D, Temp J, Seitz V, Kloner M, Negrete R, Rodriguez-Gaztelumendi A, Weber M, Machelska H, Stein C. pKa of opioid ligands as a discriminating factor for side effects. Sci Rep 2019;9:19344.
Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10:447–85.
Fullerton EF, Doyle HH, Murphy AZ. Impact of sex on pain and opioid analgesia: a review. Curr Opin Behav Sci 2018;23:183–90.
Galligan JJ, Sternini C. Insights into the role of opioid receptors in the GI tract: experimental evidence and therapeutic relevance. Handb Exp Pharmacol 2017;239:363–78.
Gaudreau JD, Gagnon P, Harel F, Roy MA, Tremblay A. Psychoactive medications and risk of delirium in hospitalized cancer patients. J Clin Oncol 2005;23:6712–8.
Goodman WA, Havran HL, Quereshy HA, Kuang S, De Salvo C, Pizarro TT. Estrogen receptor α loss-of-function protects female mice from DSS-induced experimental colitis. Cell Mol Gastroenterol Hepatol 2018;5:630–33.e1.
Guerrero-Alba R, Valdez-Morales EE, Jiménez-Vargas NN, Bron R, Poole D, Reed D, Castro J, Campaniello M, Hughes PA, Brierley SM, Bunnett N, Lomax AE, Vanner S. Co-expression of μ and δ opioid receptors by mouse colonic nociceptors. Br J Pharmacol 2018;175:2622–34.
He SF, Jin SY, Yang W, Pan YL, Huang J, Zhang SJ, Zhang L, Zhang Y. Cardiac μ-opioid receptor contributes to opioid-induced cardioprotection in chronic heart failure. Br J Anaesth 2018;121:26–37.
Huynh E, Penney J, Caswell J, Li J. Protective effects of protegrin in dextran sodium sulfate-induced murine colitis. Front Pharmacol 2019;10:156.
Jaramillo-Polanco J, Lopez-Lopez C, Yu Y, Neary E, Hegron A, Canals M, Bunnett NW, Reed DE, Lomax AE, Vanner SJ. Opioid-induced pronociceptive signaling in the gastrointestinal tract is mediated by delta-opioid receptor signaling. J Neurosci 2022;42:3316–28.
Jiménez-Vargas NN, Yu Y, Jensen DD, Bok DD, Wisdom M, Latorre R, Lopez C, Jaramillo-Polanco JO, Degro C, Guzman-Rodriguez M, Tsang Q, Snow Z, Schmidt BL, Reed DE, Lomax AE, Margolis KG, Stein C, Bunnett NW, Vanner SJ. Agonist that activates the μ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects. Gut 2021;71:695–704.
Kalvass JC, Olson ER, Cassidy MP, Selley DE, Pollack GM. Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC 50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther 2007;323:346–55.
Katagiri N, Sakai R, Izutsu T, Kawana H, Sugino S, Kido K. Postoperative pain management in patients with ulcerative colitis. Anesth Prog 2020;67:158–63.
Khanna AK, Bergese SD, Jungquist CR, Morimatsu H, Uezono S, Lee S, Ti LK, Urman RD, McIntyre R, Tornero C, Dahan A, Saager L, Weingarten TN, Wittmann M, Auckley D, Brazzi L, Le Guen M, Soto R, Schramm F, Ayad S, Kaw R, Di Stefano P, Sessler DI, Uribe A, Moll V, Dempsey SJ, Buhre W, Overdyk FJ, Tanios M, Rivas E, Mejia M, Elliott K, Ali A, Fiorda-Diaz J, Carrasco-Moyano R, Mavarez-Martinez A, Gonzalez-Zacarias A, Roeth C, Kim J, Esparza-Gutierrez A, Weiss C, Chen C, Taniguchi A, Mihara Y, Ariyoshi M, Kondo I, Yamakawa K, Suga Y, Ikeda K, Takano K, Kuwabara Y, Carignan N, Rankin J, Egan K, Waters L, Sim MA, Lean LL, Liew QEL, Siu-Chun Law L, Gosnell J, Shrestha S, Okponyia C, Al-Musawi MH, Gonzalez MJP, Neumann C, Guttenthaler V, Männer O, Delis A, Winkler A, Marchand B, Schmal F, Aleskerov F, Nagori M, Shafi M, McPhee G, Newman C, Lopez E, Har SM, Asbahi M, Nordstrom McCaw K, Theunissen M, Smit-Fun V. Prediction of opioid-induced respiratory depression on inpatient wards using continuous capnography and oximetry: an international prospective, observational trial. Anesth Analg 2020;131:1012–24.
Kim JJ, Shajib MS, Manocha MM, Khan WI. Investigating intestinal inflammation in DSS-induced model of IBD. J Visual Exp 2012;:3678.
Lama A, Provensi G, Amoriello R, Pirozzi C, Rani B, Mollica MP, Raso GM, Ballerini C, Meli R, Passani MB. The anti-inflammatory and immune-modulatory effects of OEA limit DSS-induced colitis in mice. Biomed Pharmacother 2020;129:110368.
López-Estévez S, Gris G, de la Puente B, Carceller A, Martínez V. Intestinal inflammation-associated hypersensitivity is attenuated in a DSS model of colitis in Sigma-1 knockout C57BL/6 mice. Biomed Pharmacother 2021;143:112126.
Meyer KA, Kammerling EM, Amtman L, Koller M, Hoffman SJ. pH studies of malignant tissues in human beings. Cancer Res 1948;8:513–8.
Minami K, Hasegawa M, Ito H, Nakamura A, Tomii T, Matsumoto M, Orita S, Matsushima S, Miyoshi T, Masuno K, Torii M, Koike K, Shimada S, Kanemasa T, Kihara T, Narita M, Suzuki T, Kato A. Morphine, oxycodone, and fentanyl exhibit different analgesic profiles in mouse pain models. J Pharmacol Sci 2009;111:60–72.
Niccum B, Moninuola O, Miller K, Khalili H. Opioid use among patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021;19:895–907.e4.
Nugent SG, Kumar D, Rampton DS, Evans DF. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut 2001;48:571–7.
Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 1990;98:694–702.
Park YH, Kim N, Shim YK, Choi YJ, Nam RH, Choi YJ, Ham MH, Suh JH, Lee SM, Lee CM, Yoon H, Lee HS, Lee DH. Adequate dextran sodium sulfate-induced colitis model in mice and effective outcome measurement method. J Cancer Prev 2015;20:260–7.
Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417–29.
Rodriguez-Gaztelumendi A, Spahn V, Labuz D, MacHelska H, Stein C. Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain. PAIN 2018;159:2277–84.
Rohani N, Hao L, Alexis MS, Joughin BA, Krismer K, Moufarrej MN, Soltis AR, Lauffenburger DA, Yaffe MB, Burge CB, Bhatia SN, Gertler FB. Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Cancer Res 2019;79:1952–66.
Rosset A, Spadola L, Ratib O. OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 2004;17:205–16.
Schiedler MG. Sigmoid intramural pH for prediction of ischemic colitis during aortic surgery. Arch Surg 1987;122:881.
Schirbel A, Reichert A, Roll S, Baumgart DC, Büning C, Wittig B, Wiedenmann B, Dignass A, Sturm A. Impact of pain on health-related quality of life in patients with inflammatory bowel disease. World J Gastroenterol 2010;16:3168–77.
Sosunov EA, Anyukhovsky EP, Sosunov AA, Moshnikova A, Wijesinghe D, Engelman DM, Reshetnyak YK, Andreev OA. pH (low) insertion peptide (pHLIP) targets ischemic myocardium. Proc Natl Acad Sci U S A 2013;110:82–6.
Spahn V, Del Vecchio G, Labuz D, Rodriguez-Gaztelumendi A, Massaly N, Temp J, Durmaz V, Sabri P, Reidelbach M, Machelska H, Weber M, Stein C. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017;355:966–9.
Spahn V, Del Vecchio G, Rodriguez-Gaztelumendi A, Temp J, Labuz D, Kloner M, Reidelbach M, Machelska H, Weber M, Stein C. Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist. Sci Rep 2018;8:8965.
Stein C. New concepts in opioid analgesia. Expert Opin Investig Drugs 2018;27:765–75.
Sternini C, Patierno S, Selmer IS, Kirchgessner A. The opioid system in the gastrointestinal tract. Neurogastroenterol Motil 2004;16:3–16.
Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician 2006;74:1347–54.
Theisen MM, Schlottmann S, August C, Herzog C, Theilmeier G, Maas M, Blumenstiel JM, Weber TP, Van Aken HK, Kaerlein KT. Detection and distribution of opioid peptide receptors in porcine myocardial tissue. Pharmacol Res 2014;84:45–9.
Urman RD, Khanna AK, Bergese SD, Buhre W, Wittmann M, Le Guen M, Overdyk FJ, Di Piazza F, Saager L. Postoperative opioid administration characteristics associated with opioid-induced respiratory depression: results from the PRODIGY trial. J Clin Anesth 2021;70:110167.
Wallace JL, Keenan CM. An orally active inhibitor of leukotriene synthesis accelerates healing in a rat model of colitis. Am J Physiol Gastrointest Liver Physiol 1990;258:G527–34.
Yao L, Daniels J, Moshnikova A, Kuznetsov S, Ahmed A, Engelman DM, Reshetnyak YK, Andreev OA. pHLIP peptide targets nanogold particles to tumors. Proc Natl Acad Sci U S A 2013;110:465–70.
Yu Y, Daly DM, Adam IJ, Kitsanta P, Hill CJ, Wild J, Shorthouse A, Grundy D, Jiang W. Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel. Neurogastroenterol Motil 2016;28:1465–79.
Yu Y, Tsang QK, Jaramillo-Polanco J, Lomax AE, Vanner SJ, Reed DE. Cannabinoid 1 and mu-opioid receptor agonists synergistically inhibit abdominal pain and lack side effects in mice. J Neurosci 2022;42:6313–24.
Zhai Z, Zhang F, Cao R, Ni X, Xin Z, Deng J, Wu G, Ren W, Yin Y, Deng B. Cecropin A alleviates inflammation through modulating the gut microbiota of C57BL/6 mice with DSS-induced IBD. Front Microbiol 2019;10:1595.