Chronic postoperative pain occurs in up to 50% of patients following major surgery and up to 10% of patients following less invasive minor surgery. Invasive surgeries typically produce a larger area of tissue damage accompanied by a prolonged healing time, which may in turn induce complex spinal cord changes (central plasticity) that increase the risk for development of chronic post-surgical pain. Timely and adequate local/peripheral treatment seems a logical strategy to prevent the development of persistent postoperative pain. Migrating macrophages at the site of injury orchestrate the resolution of inflammation and wound healing by acquiring a M2 phenotype (enhancement of ED2/CD163 expression and mannose receptor expression and activity). We propose to target macrophages via mannose receptors using polyethylenimine (PEI) nanoparticles grafted with a mannose ligand (Man-PEI) to induce ED2/CD163 gene expression. This state-of- the art nanotechnology approach has been used successfully to treat HIV-positive patients, supporting the translational value of this proposal. We have shown that genetic induction of ED2/CD163 using nanoparticles in murine monocytes induced an anti-inflammatory cellular phenotype characterized by a reduction of mitogen activated protein kinase (MAPK) activation, namely ERK), p38, and p- Jun-amino-terminal kinase (p-JNK), and pro-inflammatory cytokine release. In patients, the regulation of MAPKs reduces acute postoperative and chronic neuropathic pain, which adds clinical relevance to our studies. We hypothesize that the induction of ED2/CD163 gene in human macrophages using mannosylated nanoparticles will reduce the activation of ERK, p38 and JNK, and the release of pro-inflammatory effectors, which will prevent the development of persistent postsurgical pain in a rat model. We will follow these specific aims: 1) Optimization of nanotechnology-based ED2/CD163 induction in human macrophages (efficiency of transfection and gene induction);2) Assessment of nanotechnology-based ED2/CD163 induction in macrophage response patterns following LPS or interleukin (IL)-6-stimulated inflammation (reduction of MAPK activation and re-balance of pro- and anti-inflammatory factors);3) Determination of the behavioral and molecular effects of in vivo ED2/CD163 induction using nanoparticles in a rat model of persistent postsurgical pain (prevention of postoperative pain by inducing an anti-inflammatory phenotype in surgical macrophages). These studies will set the foundation for testing this technology in clinical trials in patients undergoing major surgeries. This is a grant composed by a team of clinical and basic researchers in nanotechnology and pain. It proposes novel, innovative and highly translational research under the direction of a productive NIH funded investigator who has relocated to an AREA eligible school to help build a culture of biomedical and health- related research. This proposal has been designed to provide undergraduate students with high quality biomedical research experiences that will prepare the students for biomedical sciences graduate programs. extracellular signal-regulated kinase (
Many common surgical procedures are known to induce a chronic pain state in humans. Due to the substantial economic and social impact of persistent postsurgical pain and because there are limited treatment options for this condition, the medical community needs novel and more effective therapies to prevent the development of chronic postoperative pain. The proposed studies will provide the foundation for a new therapeutic strategy that has the potential to reduce the incidence of chronic pain following major surgery.