Receptors in Endosomes Mediate Chronic Pain Associated with Trauma, Inflammation, and Stress: Non-Opioid Targets for Sustained Relief of Pain
Abstract
G-protein coupled-receptors (GPCRs) mediate pain. Damaged and diseased tissue secrete proteases that activate a GPCR,protease-activated receptor-2 (PAR2) on sensory neurons. The activated sensory neurons release neuropeptides including substance P (SP) and calcitonin gene-related peptide (CGRP). SP activates the neurokinin-1 receptor (NK1R) and CGRP activates calcitonin-like receptor (CLR), which produces pain. Endocytosis, which is the process of intracellular uptake of plasma membrane receptors, terminates plasma membrane signaling of GPCRs; however, evidence, including work supported by our original Peer Reviewed Medical Research Program (PRMRP) Award, indicates that GPCRs in intracellular sorting organelles, termed endosomes, can generate sustained signals that govern the transition from acute to chronic pain. PAR2 is implicated in pain associated with inflammatory bowel disease (IBD). Endosomal signaling of PAR2 in trigeminal nociceptors and Schwann cells mediates post-traumatic headache (PTH). For the Expansion Award we developed encapsulated small molecule GPCR antagonists, including FDA-approved drugs, into nanoparticles (NPs). Our NPs offer a fresh approach for the treatment of chronic pain, especially pain related to IBD and PTH, which disproportionately affects military personnel and veterans.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1220825
Entities
People
- Nigel W Bunnett
Organizations
- New York University