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 U.S. Food and Drug Administration (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. Our Expansion Award addresses three FY21 PRMRP Topic Areas, along with the respective Areas of Encouragement: Non-Opioid Pain Management: Our work investigates pain-related GPCRs that are distinct from opioids. We use NPs to deliver drugs that block the action of GPCRs in endosomes. We will develop and test non-opioid, non-addictive pain management for patients with limited access to skilled providers and resources, including battlefield and resource-limited environments. Sustained Release Drug Delivery: We have designed NPs to be dried, stable at room temperature, long-acting, potent drugs that block the pain-related receptors following internalization. We will optimize long-term sustained-release delivery of drugs for pain control following pre-hospital trauma for up to 24 hours, particularly in far-forward military operational environments. Inflammatory Bowel Diseases: The NPs designed for our Expansion Award enable us to block the endocytosed pain-related receptors activated by proteases that result from dysbiosis and the host inflammatory colonic infiltrate. We leverage our NPs to prevent and treat IBD. Our Expansion Award consists of three aims. In Aim 1, we will develop NP-encapsulated PAR2 and CLR antagonists optimized for sustained drug release, storage stability, endosomal uptake and retention, and antagonism of eGPCR signaling. In Aim 2, we will investigate whether PAR2 signals from endosomes in nerve fibers that innervate the colon to mediate IBD pain and neurogenic inflammation. In Aim 3, we will investigate whether PAR2 and CLR signal from endosomes of trigeminal neurons, and the Schwann cells that ensheath the neurons, to mediate PTH pain and neurogenic inflammation. We expect that the work we propose in the Expansion Award will provide NPs that are stable without refrigeration in resource-limited environments and for immediate delivery in situations with limited access to skilled providers. The NPs could alleviate pain in millions of Service personnel, Veterans, and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210238
Entities
People
- Nigel W Bunnett
Organizations
- New York University
- United States Army