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

目前使用的止痛药有主要的副作用，如胃肠道溃疡，出血，嗜睡，便秘，耐受性或成瘾。这个翻译项目探索了在动物和人类中没有这种不良影响的疼痛控制的新方法。浸润发炎组织的免疫细胞产生并释放阿片肽。这些肽激活感觉神经末梢上的阿片受体并抑制神经元兴奋性，导致镇痛。与传统的外源性激动剂相比，内源性阿片类药物诱导受体下调、耐受或反常兴奋效应的潜力降低，这是由于受体处的外源性激动剂浓度非生理性高。我们的目的是通过刺激内源性阿片类物质的分泌或抑制内源性阿片类物质的酶降解来产生镇痛和抗炎作用。在炎性疼痛的动物模型和关节炎患者中，我们将检查疼痛、阿片肽的释放和细胞外浓度，这些阿片肽由肾上腺素能受体配体和肽酶抑制剂调节。在患者中，我们还将评估生活质量，炎症参数和副作用。

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.