Abstract
The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Cav2.2, Itgam/Cd11b, Scn9a/Nav1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE2 at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.
Highlights
Peripheral nerve injury underlying neuropathic pain affects over 100 million Americans and costs roughly $600 billion annually [1]
First demonstrated by Bennett and Xie [2] chronic constriction injury (CCI) of a peripheral nerve is known to induce hypersensitivity, which is interpreted as neuropathic pain caused by the neuroinflammation
The effects of celecoxib-loaded nanoemulsion (CXB-NE) treatment on CCI rats was determined by using the paw withdrawal threshold when probed with von Frey filaments of increasing diameter [33,34]
Summary
Peripheral nerve injury underlying neuropathic pain affects over 100 million Americans and costs roughly $600 billion annually [1]. The initial immune response consists of infiltration of immune cells to the site of injury at the sciatic nerve, activation of immune and glial cells, and Wallerian degeneration of distal nerve fibers [11,12,13]. This process includes the recruitment of circulating monocytes to the site of injury, which release pro-inflammatory cytokines, chemokines, trophic and growth factors that cause neuronal hypersensitivity in the periphery [14]. The injured neurons and Schwann cells produce and release inflammatory mediators [16] such as cytokines, chemokines, neurotrophic factors, Substance P, and prostanoids that all contribute to the neuroinflammatory milieu
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