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Receptors in Endosomes Mediate Chronic Pain Associated with Trauma and Stress: Non-Opioid Targets for Pain
The grant seeks to determine whether G protein-coupled receptors (GPCRs) in endosomes, rather than at the plasma membrane, are mediators and therapeutic targets for chronic pain. Aim 1 examines whether GPCRs in endosomes control activity of ion channels and expression of genes that induce sustained neuronal excitation. Aim 2 determines whether endosomally-targeted antagonists inhibit channel activity, gene expression and hyperexcitability of neurons. Aim 3 evaluates the therapeutic potential of endosomally-targeted GPCR antagonists in trauma- and stress-induced pain relevant to military personnel. Progress has been made in all aims. Neuropeptides (substance P, calcitonin gene-related peptide) and proteases (trypsin) stimulated GPCR endocytosis and evoked sustained signals and hyperexcitability in pain-sensing neurons. Dynamin and clathrin inhibitors suppressed endocytosis, signaling and hyperexcitability. Therapies have been developed to block endosomal signaling and evaluated in preclinical models of trauma- and stress-induced pain. Therapies include: dynamin and clathrin inhibitors; lipid-conjugated antagonists that accumulate in endosomes; antagonists encapsulated into nanoparticles that disassemble in acidic endosomes. These antagonists effectively reversed nociception in preclinical models of visceral pain, migraine pain, and nerve injury pain. They were more effective than conventional antagonists of plasma membrane GPCRs. Thus, endosomal GPCRs have been identified as major mediators and therapeutic targets for chronic pain.
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