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.