Sunday 3 June, 1100-1200H, Red Room 2
In this session, Professor Christoph Stein (Director of the Clinic for Anesthesiology and Operational Intensive Medicine at the Charité Hospital, Berlin, Germany) will present on opioid analgesia without side effects.
“Indiscriminate activation of opioid receptors by conventional opioid drugs (morphine, fentanyl) provides pain relief but also central and intestinal side effects such as respiratory depression, sedation, addiction, nausea and constipation,” says Professor Stein. “Novel strategies to avoid adverse effects include the design of ‘biased’ agonists and the selective activation of opioid receptors at the peripheral source of pain generation, that is within injured tissue. The latter can be achieved either by exploiting pathological (rather than physiological) pharmacodynamics of opioid receptor-ligand interactions, or by altering drug distribution (pharmacokinetics).”
Using computer simulations at low pH, a hallmark of injured tissue, Professor Stein’s team designed an agonist (NFEPP) that, due to its low pKa, selectively activates peripheral mu-opioid receptors in injured/inflamed tissue, that is at the source of pain generation. Unlike conventional opioids, NFEPP showed pH-sensitive binding, G-protein subunit dissociation, and cAMP inhibition in vitro, and it produced injury-restricted analgesia in different models of inflammatory pain.
In collaboration with chemists, the team used another strategy applying a cleavable linker to attach morphine to a polyglycerol-based nanocarrier. This conjugate (PG-M) was devised to selectively release morphine in inflamed tissue and to preclude blood-brain barrier permeation due to its high molecular weight and hydrophilicity. Preclinical experiments showed that this construct exclusively activated peripheral opioid receptors to produce analgesia in injured tissue.
Professor Stein concludes: “Both NFEPP and PG-M produced analgesic effects of similar magnitude to conventional opioids without exhibiting respiratory depression, sedation, constipation or addiction potential.”
The other half of this session, on ‘new devices – can they measure nociception’ – will be presented by Dr Jean-Pierre Estebe¸ University Hospital of Rennes, France.
References: Science 2017; 355:966-9; eLife 2017;6:e27081