Share this article on:

Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

Rodriguez-Gaztelumendi, Antonio; Spahn, Viola; Labuz, Dominika; Machelska, Halina; Stein, Christoph*

doi: 10.1097/j.pain.0000000000001328
Research Paper: PDF Only

Recently, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a newly designed μ-opioid receptor (MOR) agonist with a low pKa, has been shown to produce injury-restricted analgesia in models of inflammatory and postoperative pain, without exhibiting typical opioid side effects. Here, we investigated MOR binding of NFEPP in brain and dorsal root ganglia, pH in injured tissues, and the analgesic efficacy of NFEPP compared with fentanyl in a chronic constriction injury model of neuropathic pain, and in the acetic acid–induced abdominal writhing assay in rats. Binding experiments revealed significantly lower affinity of NFEPP compared with fentanyl at pH 7.4. In vivo, pH significantly dropped both at injured nerves after chronic constriction injury and in the abdominal cavity after acetic acid administration. Intravenous NFEPP as well as fentanyl dose-dependently diminished neuropathy-induced mechanical and heat hypersensitivity, and acetic acid–induced abdominal constrictions. In both models, NFEPP-induced analgesia was fully reversed by naloxone methiodide, a peripherally restricted opioid receptor antagonist, injected at the nerve injury site or into the abdominal cavity. Our results indicate that NFEPP exerts peripheral opioid receptor–mediated analgesia exclusively in damaged tissue in models of neuropathic and abdominal pain.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

The newly designed, pH-dependent opioid agonist NFEPP induced analgesia exclusively through peripheral opioid receptors in models of neuropathic and abdominal pain.

Department of Anesthesiology and Critical Care Medicine, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Dr. Rodriguez-Gaztelumendi is now with the Department of Drug Discovery and In Vitro Pharmacology, Laboratorios Dr. Esteve, Parc Científic de Barcelona, Barcelona, Spain

Corresponding author. Address: Department of Anesthesiology and Critical Care Medicine, Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. Tel.: +49-30-450551522; fax: +40-30-450551939. E-mail address: christoph.stein@charite.de (C. Stein).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received January 05, 2018

Received in revised form June 20, 2018

Accepted June 26, 2018

© 2018 International Association for the Study of Pain