Safer analgesics by modulation of the kappa-opioid receptor

• Applicant: Professor Dr. Gerhard Wolber
• Subject Area: Pharmacy
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 435233773

With a prevalence of 20-30% worldwide, chronic pain affects more people than heart disease, cancer and diabetes combined, and will certainly continue to grow as the population ages. Incapacitating pain is a constant backdrop in daily life, resulting in personal suffering, high healthcare costs and economic burden for the society. Pain relief and management can be achieved via binding and activation of opioid receptors by opioid analgesics. While currently available opioids, such as morphine, oxycodone and fentanyl, are agonists at the mu-opioid receptor (MOR), and effectively reduce pain, they cause also serious side effects (i.e. constipation, respiratory depression, sedation, nausea, tolerance and dependence). Prescription opioid misuse and addiction is a rapidly escalating epidemic in the past years, resulting in increased opioid-related overdose deaths. Therefore, research efforts are needed towards overcoming the limitations of present therapies, with the final goal to improve treatment efficacy, patient compliance and to reduce complications. The rationale of the planned research is based on (a) the kappa-opioid receptor (KOR) an opioid receptor subtype that can be targeted to effectively reduce pain without the risks of physical dependence and addictive potential associated with currently used MOR agonists, (b) the recent elucidation of the active structure of KOR, and (c) the contemporary concept of biased agonism and the therapeutic promise of biased agonism for better pain treatment. Recent data revealed the exciting prospect that biased KOR agonists, preferentially activating G protein signaling, may be identified as a new class of analgesic drugs with fewer adverse effects, and without liability for addiction and abuse. The present project comprises basic research as computational and experimental work undertaken in the fields of pain research and KOR pharmacology aiming to identify novel, effective, safe and nonaddictive scientifically proven opioid drugs at the KOR with target-oriented pharmacology (i.e. G protein-biased agonism) for pain treatment, and to assess functional selectivtiy and structural and molecular determinants that can form the basis for an improvement of the benefit/risk index. The outcome of this project will expand the understanding on ligand-receptor interaction, molecular mode of action and KOR-mediated signaling pathways towards identifying better tolerated and more efficacious analgesic drugs. Besides the scientific aspect, this project entails medical, social and economic perspectives on a long-term basis. The outlooks of this project are of high relevance due to the increasing number of patients suffering from chronic pain.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Privatdozentin Dr. Mariana Spetea