Locating the Site of Neuropathic Pain In Vivo Using MMP-12-Targeted Magnetic Nanoparticles.

Syeda Fabeha Husain,Tao Hu,Z Q G Liau,Raymond W M Lam,Keiji Nagata,Yulin Lam,Sanjay Khanna,Hee-Kit Wong,Roger C M Ho,Kishore Bhakoo,Michael W F Ng

doi:10.1155/2019/9394715

Abstract

Neuropathic pain remains underrecognised and ineffectively treated in chronic pain sufferers. Consequently, their quality of life is considerably reduced, and substantial healthcare costs are incurred. The anatomical location of pain must be identified for definitive diagnosis, but current neuropsychological tools cannot do so. Matrix metalloproteinases (MMP) are thought to maintain peripheral neuroinflammation, and MMP-12 is elevated particularly in such pathological conditions. Magnetic resonance imaging (MRI) of the peripheral nervous system has made headway, owing to its high-contrast resolution and multiplanar features. We sought to improve MRI specificity of neural lesions, by constructing an MMP-12-targeted magnetic iron oxide nanoparticle (IONP). Its in vivo efficiency was evaluated in a rodent model of neuropathic pain, where the left lumbar 5 (L5) spinal nerve was tightly ligated. Spinal nerve ligation (SNL) successfully induced mechanical allodynia, and thermal hyperalgesia, in the left hind paw throughout the study duration. These neuropathy characteristics were absent in animals that underwent sham surgery. MMP-12 upregulation with concomitant macrophage infiltration, demyelination, and elastin fibre loss was observed at the site of ligation. This was not observed in spinal nerves contralateral and ipsilateral to the ligated spinal nerve or uninjured left L5 spinal nerves. The synthesised MMP-12-targeted magnetic IONP was stable and nontoxic in vitro. It was administered onto the left L5 spinal nerve by intrathecal injection, and decreased magnetic resonance (MR) signal was observed at the site of ligation. Histology analysis confirmed the presence of iron in ligated spinal nerves, whereas iron was not detected in uninjured left L5 spinal nerves. Therefore, MMP-12 is a potential biomarker of neuropathic pain. Its detection in vivo, using IONP-enhanced MRI, may be further developed as a tool for neuropathic pain diagnosis and management.

Highlights

Back pain is the highest reported pain condition and progresses to chronic lower back pain in two-thirds of patients.ese patients present nociceptive and/or neuropathic components, but the later component is usually underrecognised [1]
MWL and thermal withdrawal latency (TWL) difference of sham rats did not differ between the three test points (Figures 1(b) and 1(c)). us, mechanical allodynia and thermal hyperalgesia of the left side was evident in Spinal nerve ligation (SNL) rats until their respective endpoints [24]
In SNL rats, CD68 and Matrix metalloproteinases (MMP)-12 staining in the left L4, left L6, and right lumbar 5 (L5) spinal nerves were lower than the left L5 spinal nerve (Figure 2)

Summary

Introduction

Back pain is the highest reported pain condition and progresses to chronic lower back pain in two-thirds of patients. Current screening tools to assess nerve damage are neuropsychological in nature, which include questionnaires and various electrodiagnostic tests They cannot provide conclusive evidence for neuropathic pain or locate the exact paingenerating site [3]. IONP has been used to observe macrophage migration into experimentally injured sciatic nerves in vivo [11, 13]. Macrophage factors, including MMPs, may instead present as potential targets for in vivo IONPbased MRI. We hypothesise that elevated MMP-12 activity at the site of nerve injury can be detected in vivo. An MMP-12-targeted magnetic IONP may be able to locate the pain-generating site by MRI. E last aim was to examine in vivo MRI of animals receiving the MMP-12-targeted magnetic IONP and to verify IONP uptake by histology analysis of spinal nerves

Materials and Methods

Results and Discussion

Conclusions