Abstract
We explored the immune neuropathology underlying multi-day relief from neuropathic pain in a rat model initiated at the sciatic nerve, by using a nanoemulsion-based nanomedicine as a biological probe. The nanomedicine is theranostic: both therapeutic (containing celecoxib drug) and diagnostic (containing near-infrared fluorescent (NIRF) dye) and is small enough to be phagocytosed by circulating monocytes. We show that pain-like behavior reaches a plateau of maximum hypersensitivity 8 days post-surgery, and is the rationale for intravenous delivery at this time-point. Pain relief is evident within 24 h, lasting approximately 6 days. The ipsilateral sciatic nerve and associated L4 and L5 dorsal root ganglia (DRG) tissue of both nanomedicine and control (nanoemulsion without drug) treated animals was investigated by immunofluorescence and confocal microscopy at the peak of pain relief (day-12 post-surgery), and when pain-like hypersensitivity returns (day-18 post-surgery). At day-12, a significant reduction of infiltrating macrophages, mast cells and mast cell degranulation was observed at the sciatic nerve following treatment. In the DRG, there was no effect of treatment at both day-12 and day-18. Conversely, at the DRG, there is a significant increase in macrophage infiltration and mast cell degranulation at day-18. The treatment effect on immune pathology in the sciatic nerve was investigated further by assessing the expression of macrophage cyclooxygenase-2 (COX-2)—the drug target—and extracellular prostaglandin E2 (PGE2), as well as the proportion of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. At day-12, there is a significant reduction of COX-2 positive macrophages, extracellular PGE2, and a striking reversal of macrophage polarity. At day-18, these measures revert to levels observed in control-treated animals. Here we present a new paradigm of immune neuropathology research, by employing a nanomedicine to target a mechanism of neuropathic pain—resulting in long-lasting pain relief--whilst revealing novel immune pathology at the injured nerve and associated DRG.
Highlights
Pain remains the most pervasive reason for medical visits worldwide and affects more people than cancer, heart disease, and diabetes combined (NIH, 2010)
We present a new paradigm of immune neuropathology research, by employing a nanomedicine to target a mechanism of neuropathic pain—resulting in long-lasting pain relief--whilst revealing novel immune pathology at the injured nerve and associated dorsal root ganglia (DRG)
Our results suggest that the central driver of nanomedicine chronic pain relief is a shift towards an M2 macrophage phenotype, via attenuation of intracellular macrophage COX-2
Summary
Pain remains the most pervasive reason for medical visits worldwide and affects more people than cancer, heart disease, and diabetes combined (NIH, 2010). We sought to further our understanding of the immune-cell pathology underlying neuropathic pain by utilizing the chronic constriction injury (CCI) rat model [7] In this model, an inflammatory response is produced by loosely tied chromic gut ligatures on the right sciatic nerve, causing swelling and subsequent constriction of the nerve. The inflamed nerve is infiltrated by a complex milieu of immune cells, inflammatory mediators [64] and signaling molecules, resulting in nociceptor sensitization, and causing persistent pain [21]. This inflammatory response is largely driven by the infiltration of macrophages [33, 43], which express the cyclooxygenase-2 (COX-2) enzyme. Rats exhibit progressive hypersensitive painlike behavior reaching a maximum approximately 8 days following surgery [31, 63, 64]
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