Opioid analgesia in inflammation: activation by catecholamines and inhibitors of opioid peptide-degrading enzymes

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Currently used pain medications have major side effects such as gastrointestinal ulcers, bleeding, drowsiness, constipation, tolerance or addiction. This translational project explores novel ways of pain control without such adverse effects in animals and humans. Immune cells infiltrating inflamed tissue produce and release opioid peptides. These peptides activate opioid receptors on peripheral terminals of sensory nerves and inhibit neuronal excitability, resulting in analgesia. Compared to conventional exogenous agonists, endogenous opioids have a reduced potential of inducing receptor-downregulation, tolerance or paradoxical excitatory effects due to unphysiologically high exogenous agonist concentrations at the receptor. We aim at producing analgesia and anti-inflammatory effects by stimulating the secretion or by inhibiting the enzymatic degradation of endogenous opioids. In an animal model of inflammatory pain and in patients with inflamed joints we will examine pain, release and extracellular concentrations of opioid peptides, modulated by adrenergic receptor ligands and by peptidase inhibitors. In patients we will also assess quality of life, inflammatory parameters and side effects.