PainRelief.com Interview with:
Prof. Dr. Christoph Stein
Institut für Experimentelle Anaesthesiologie
Charité Campus Benjamin Franklin
Freie Universität Berlin
PainRelief.com: What is the background for this study? What are the main findings?
Response: Our group has studied the biology and pharmacology of opioid receptors on peripheral sensory neurons (i.e. outside the central or intestinal nervous system) for over 25 years. We have always aimed at finding mechanisms and opioid receptor ligands that can be developed into drugs inhibiting pain without eliciting typical adverse effects of conventional opioids such as apnoea, addiction, sedation or constipation.
From our previous work we knew that the selective activation of opioid receptors on peripheral sensory neurons can produce powerful pain relief in animals and human patients. Those analgesic effects are particularly strong in pain caused by tissue injury and inflammation (e.g. postoperative pain, arthritis). Together with mathematicians (Dr. Marcus Weber) at the Zuse Institute Berlin, we started out with computer simulations examining the interaction between opioid ligands and receptors in normal (noninflamed) and inflamed environments. These studies indicated a stronger binding of conventional opioid ligands (morphine, fentanyl) to opioid receptors at increased proton concentrations (i.e. low pH, as present in acidotic/inflamed tissue). We also knew that the protonation of a tertiary amine in the ligand is required for opioid receptor activation. Using those in silico simulations, we now designed a new ligand (NFEPP) that is only protonated (and capable of activating opioid receptors) at low pH, but not at normal pH (as in brain and intestinal wall). After synthesis of NFEPP (and similar derivatives) by a contractor we tested them in vitro and in vivo. NFEPP produced opioid receptor activation and analgesia selectively at low pH/tissue inflammation (as present in nerve injury/neuropathy and abdominal inflammation) without eliciting respiratory depression, addiction potential, sedation or constipation.
PainRelief.com: What should readers take away from your report?
Response: Detrimental side effects of both conventional opioids and nonsteroidal analgesics (gastrointestinal ulcers, bleeding, stroke, heart attack) can be avoided by the new compounds.
PainRelief.com: What recommendations do you have for future research as a result of this work?
Response: We will now investigate the interaction of opioid ligands and receptors in inflamed environments in more detail and concentrate on conformational changes of opioid receptors. We are seeking investors or partners in the pharmaceutical industry to develop our new compounds towards clinical phase 1 and 2 trials.
PainRelief.com: Is there anything else you would like to add?
Response: These data were published in Science 2017; 355(6328):966-9; Sci Rep 2018;8(1):8965; Pain 2018, PMID: 29994988
- Antonio Rodriguez-Gaztelumendi, Viola Spahn, Dominika Labuz, Halina Machelska, Christoph Stein. Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain. PAIN, 2018; 1 DOI: 10.1097/j.pain.0000000000001328
- Viola Spahn, Giovanna Del Vecchio, Antonio Rodriguez-Gaztelumendi, Julia Temp, Dominika Labuz, Michael Kloner, Marco Reidelbach, Halina Machelska, Marcus Weber, Christoph Stein. Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-27313-4
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