Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gα_i/o and β-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.

G蛋白偶联受体是否从内体发出信号来控制重要的病理生理过程，是否为治疗靶点尚不确定。我们报告说，来自发炎结肠的阿片类药物可激活伤害感受器内体中的δ-阿片类药物受体（DOPr）。结肠炎患者和小鼠发炎的结肠粘膜的活检样品释放出阿片样物质，该阿片样物质激活了伤害感受器上的DOPr，导致兴奋性持续下降。DOPr激动剂抑制机械敏感的结肠伤害感受器。DOPr通过蛋白激酶C（PKC）和细胞外信号调节激酶（ERK）途径的胞吞和内体信号传导介导了内源性阿片类药物和DOPr激动剂的持续抑制作用。DOPr激动剂刺激了Gαi _{/ o}的募集和β-arrestin1/ 2对内体。对间隔信号的分析表明，DOPr内吞作用需要激活质膜以及细胞质和核中ERK的PKC。我们探索了一种纳米颗粒递送策略，以评估内体DOPr是否可能是疼痛的治疗靶标。DOPr激动剂DADLE与脂质体壳偶联以靶向DOPr阳性伤害感受器，并掺入中孔二氧化硅核中，以在酸性和还原性内体环境中释放。纳米颗粒在质膜上激活了DOPr，优先被DOPr表达细胞内吞，并被递送至DOPr阳性的早期内体。纳米颗粒引起内体中DOPr的持久活化，从而持续抑制伤害感受器兴奋性并减轻炎症性疼痛。相反，含有DOPr拮抗剂的纳米颗粒消除了DADLE的持续抑制作用。因此，内体中的DOPr是缓解慢性炎症性疼痛的内源性机制和治疗靶标。