Abstract
Chronic neuropathic pain following surgery represents a serious worldwide health problem leading to life-long treatment and the possibility of significant disability. In this study, neuropathic pain was modeled using the chronic constriction injury (CCI). The CCI rats exhibit mechanical hypersensitivity (typical neuropathic pain symptom) to mechanical stimulation of the affected paw 11 days post surgery, at a time when sham surgery animals do not exhibit hypersensitivity. Following a similar time course, TRPV1 gene expression appears to rise with the hypersensitivity to mechanical stimulation. Recent studies have shown that immune cells play a role in the development of neuropathic pain. To further explore the relationship between neuropathic pain and immune cells, we hypothesize that the infiltration of immune cells into the affected sciatic nerve can be monitored in vivo by molecular imaging. To test this hypothesis, an intravenous injection of a novel perfluorocarbon (PFC) nanoemulsion, which is phagocytosed by inflammatory cells (e.g. monocytes and macrophages), was used in a rat CCI model. The nanoemulsion carries two distinct imaging agents, a near-infrared (NIR) lipophilic fluorescence reporter (DiR) and a 19F MRI (magnetic resonance imaging) tracer, PFC. We demonstrate that in live rats, NIR fluorescence is concentrated in the area of the affected sciatic nerve. Furthermore, the 19F MRI signal was observed on the sciatic nerve. Histological examination of the CCI sciatic nerve reveals significant infiltration of CD68 positive macrophages. These results demonstrate that the infiltration of immune cells into the sciatic nerve can be visualized in live animals using these methods.
Highlights
Pain is a public health problem that has deleterious effects on social, mental, physical and economic health of its sufferers [1]
We demonstrate that constriction injury (CCI) rats exhibit symptoms of mechanical hypersensitivity, which is a hallmark of chronic pain
We demonstrate that the NIR and 19F signal is arising from CD68 positive macrophage cells carrying the nanoemulsion that infiltrate the CCI injured nerve
Summary
Pain is a public health problem that has deleterious effects on social, mental, physical and economic health of its sufferers [1]. Pain caused by injury or disease associated with the somatosensory nervous system is called neuropathic pain [2]. Recent studies have estimated that at least 6 million Americans suffer from neuropathic pain [3]. Other studies indicate that neuropathic pain is usually associated with nerve inflammation [4], which occurs when leukocytes such as macrophages infiltrate the nerve. The chronic constriction injury (CCI) rat model [5] is a wellcharacterized example of chronic peripheral neuropathic pain [6]. This model is widely used to simulate Complex Regional Pain Syndrome type II observed in humans (CRPS II, earlier called causalgia) [5]. CRPS II develops when a major peripheral nerve is injured [7] and includes persistent pain and mechanical allodynia [8]
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