Macrophage Derived Small Extracellular Vesicles to Resolve Spinal Cord Injury Induced Pain

Neuropathic pain is a common complication of spinal cord injury (SCI), characterized by symptoms of allodynia and hyperalgesia experienced at- and below the level of injury. This type of chronic pain can be spontaneous or evoked, and currently accepted therapeutics display limited efficacy. Neuroimmune interactions are thought to play a central role in the development and maintenance of neuropathic pain. Increased production of proinflammatory mediators after SCI alters the expression of voltage-gated channels on primary nociceptors, driving hypersensitivity and spontaneous activity. This results in aberrant sensory signaling extending from the peripheral dorsal root ganglia (DRG) into the spinal dorsal horn and ascending to supraspinal centers, driving neuropathic pain. Intercellular communications between infiltrating macrophages and neuronal populations in the DRG after injury have drawn considerable interest in the study of neuropathic pain, as these cells have critical contributions to both the development and resolution of chronic pain. Recent work highlights the therapeutic potential of small extracellular vesicles (sEVs) derived from lipopolysaccharide (LPS)-stimulated macrophages in preclinical models of inflammation and pain. Preliminary data from our lab revealed a dramatic resolution of established SCI-induced neuropathic pain and a more normal distribution of nociceptive primary afferents in the spinal cord after intrathecal injection of sEVs released from RAW 264.7 macrophages treated with LPS. However, how sEVs affect nociceptors and/or other cells found along the sensory neuroaxis remains to be established. We hypothesize that sEVs from LPS-stimulated macrophages attenuate aberrant nociceptor plasticity and hyperexcitability to resolve neuropathic pain after SCI via 1: direct internalization by nociceptors in the DRG, or 2: indirectly by affecting endogenous macrophage/microglia mediated mechanisms. Two specific aims have been developed to explore this hypothesis. Our first aim will utilize patch clamp electrophysiology recordings to determine how DRG nociceptors are affected by sEV administration both in vitro and in vivo. The second aim will deplete endogenous macrophages and microglia in hypersensitive SCI rats to determine whether these cells are necessary for the analgesic effect of sEV administration. The data from this proposal will explore how macrophage derived sEVs interact with the neuroimmune environment after SCI in a way that facilitates treatment of neuropathic pain. Project Number: 1F31NS147754-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Jason Wheeler | Institution: DREXEL UNIVERSITY, PHILADELPHIA, PA | Award Amount: $50,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F01A-S (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11317476