Mechanisms of Pain Hypersensitivity in a Human Skin Inflammation Model

Summary

The main goal of this double-blind, randomized, placebo-controlled crossover study is to understand the molecular mechanisms of inflammation-induced increased pain sensitivity (hyperalgesia). These mechanisms are studied using a recently established human model of skin inflammation that mimics aspects of skin infection. A localized inflammatory response in the skin of healthy volunteers is elicited by locally injecting a small, safe dose of Lipopolysaccharide (LPS), a major component of gram-negative bacteria. The study addresses three key research questions: * Role of RAGE: To investigate if certain inflammatory effects of LPS, which contribute to hyperalgesia, are mediated by a signaling pathway involving the RAGE receptor. * Pain Sensitization: To examine how skin inflammation affects pain caused by acidic stimuli, and to differentiate this from purely mechanical pain. * Role of TRPV1: To determine if the contribution of the TRPV1 ion channel to acid-induced pain is different in inflamed skin. Participants will undergo an experimental session 4.5 hours after LPS injection to measure skin blood flow (using laser speckle imaging), mechanical pain sensitivity (using specialized tweezers), and pain induced by injecting a solution, of which the pH is gradually decreasing (acid-induced pain). The study has minimal risks due to the small, safe doses of substances used ('microdosing') and aims to lay the groundwork for developing new treatments for inflammatory pain conditions.

Timeline

Start

2025-06-17

Primary completion

2025-07-11

Completion

2025-07-11

Publications

• Results Schwarz MG, Namer B, Reeh PW, Fischer MJM. TRPA1 and TRPV1 Antagonists Do Not Inhibit Human Acidosis-Induced Pain. J Pain. 2017 May;18(5):526-534. doi: 10.1016/j.jpain.2016.12.011. Epub 2017 Jan 3.
• Results Li J, Wang K, Huang B, Li R, Wang X, Zhang H, Tang H, Chen X. The receptor for advanced glycation end products mediates dysfunction of airway epithelial barrier in a lipopolysaccharides-induced murine acute lung injury model. Int Immunopharmacol. 2021 Apr;93:107419. doi: 10.1016/j.intimp.2021.107419. Epub 2021 Feb 3.
• Results Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008 Apr 14;584(1):40-8. doi: 10.1016/j.ejphar.2008.01.026. Epub 2008 Feb 5.
• Results Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, Demeyer I, Sainati S, Amlot N, Cao C, Ii M, Matsuda H, Mouri K, Cohen J. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010 Aug;38(8):1685-94. doi: 10.1097/CCM.0b013e3181e7c5c9.
• Results Kiers D, Leijte GP, Gerretsen J, Zwaag J, Kox M, Pickkers P. Comparison of different lots of endotoxin and evaluation of in vivo potency over time in the experimental human endotoxemia model. Innate Immun. 2019 Jan;25(1):34-45. doi: 10.1177/1753425918819754.
• Results Suffredini AF, Hochstein HD, McMahon FG. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O:113 endotoxin. J Infect Dis. 1999 May;179(5):1278-82. doi: 10.1086/314717.
• Results Bretag AH. Synthetic interstitial fluid for isolated mammalian tissue. Life Sci. 1969 Mar 1;8(5):319-29. doi: 10.1016/0024-3205(69)90283-5. No abstract available.
• Results Heber S, Ciotu CI, Hartner G, Gold-Binder M, Ninidze N, Gleiss A, Kress HG, Fischer MJM. TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin. Pain. 2020 Jul;161(7):1532-1541. doi: 10.1097/j.pain.0000000000001848.
• Results Nair M, Jagadeeshan S, Katselis G, Luan X, Momeni Z, Henao-Romero N, Chumala P, Tam JS, Yamamoto Y, Ianowski JP, Campanucci VA. Lipopolysaccharides induce a RAGE-mediated sensitization of sensory neurons and fluid hypersecretion in the upper airways. Sci Rep. 2021 Apr 16;11(1):8336. doi: 10.1038/s41598-021-86069-6.
• Results Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, Han D, Watanabe T, Asano M, Takasawa S, Okamoto H, Shimura S, Karasawa T, Yonekura H, Yamamoto H. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol. 2011 Mar 1;186(5):3248-57. doi: 10.4049/jimmunol.1002253. Epub 2011 Jan 26.
• Results Buters TP, Hameeteman PW, Jansen IME, van Hindevoort FC, Ten Voorde W, Grievink HW, Schoonakker M, de Kam ML, Gilroy DW, Feiss G, Rissmann R, Jansen MAA, Burggraaf J, Moerland M. Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers. Clin Pharmacol Ther. 2022 Apr;111(4):964-971. doi: 10.1002/cpt.2516. Epub 2022 Jan 6.
• Results Buters TP, Hameeteman PW, Jansen IME, van Hindevoort FC, Ten Voorde W, Florencia E, Osse M, de Kam ML, Grievink HW, Schoonakker M, Patel AA, Yona S, Gilroy DW, Lubberts E, Damman J, Feiss G, Rissmann R, Jansen MAA, Burggraaf J, Moerland M. Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers. Br J Clin Pharmacol. 2022 Feb;88(2):680-690. doi: 10.1111/bcp.14999. Epub 2021 Aug 24.

Drugs

Indications

No indication recorded.