Abstract
2904
Introduction: Voltage-gated sodium channels (Navs) in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While Nav isoforms, particularly Nav1.7, are implicated in neuropathic pain disorders, changes in the functional state and expression levels of these channels have not been extensively studied in vivo. The development of noninvasive neuroimaging tools to measure the extent of or change in pain signal transmission in vivo can help to advance both the research and treatment of neuropathic pain conditions and treatments. Radiocaine, a fluorine-18 radiotracer based on the local anesthetic lidocaine, has previously been used for cardiac Nav1.5 imaging using positron-emission tomography (PET). Because lidocaine is a non-selective Nav blocker, [18F]Radiocaine can be used to image other Nav isoforms, particularly those implicated in neuropathic injuries. In the present study, we used [18F]Radiocaine to visualize neuronal Nav expression using PET/MR in rodents that had undergone unilateral spinal nerve ligation.
Methods: [18F]Radiocaine was synthesized and formulated according to Hooker, et al. (2017). Rats underwent unilateral L5/L6 spinal nerve ligation following a procedure modified from Kim and Chung (1992). PET/MR imaging of rats with [18F]Radiocaine was performed at the acute stage (days 3–7) and the chronic stage (days 24–32) post-surgery. In order to assess the efficacy of SNL, the von Frey behavioral test was used to assess tactile allodynia in both hindlimbs of rats prior to SNL (baseline) and at the acute and chronic post-surgical stages. Additionally, whole-cell patch-clamp electrophysiology was used to assess the affinity of [19F]Radiocaine for eight isoforms of human voltage-gated sodium ion channels (hNav1.1 through hNav1.8).
Results: PET/MR imaging of rats that had undergone SNL demonstrated increased uptake of [18F]Radiocaine into the injured sciatic nerve as compared to the uninjured side at both the acute and chronic stages. At the acute stage post-surgery, PET/MR images demonstrated uptake of [18F]Radiocaine in the injured sciatic nerve was about 30% greater than uptake into the uninjured sciatic nerve (Figure 1). The uptake of radiotracer into nearby muscle tissue was significantly lower than into either sciatic nerve. At the acute stage, the von Frey test demonstrated significant tactile allodynia in the injured hindlimb, while the uninjured side was unaffected. At the chronic stage, radiotracer uptake into the injured sciatic nerve remained greater on the injured side than it was on the uninjured side (Figure 2). Notably, at the chronic stage, von Frey data demonstrated no significant difference in the allodynic response on the injured and uninjured sides. While rats had similar behavioral responses on both sides, radiotracer uptake into the injured sciatic nerve was still significantly higher than uptake on the contralateral side. Administration of intravenous lidocaine five minutes prior to [18F]Radiocaine injection at the chronic stage resulted in complete block of the [18F]Radiocaine signal in both sciatic nerves. Whole-cell patch-clamp electrophysiological studies demonstrated that [19F]Radiocaine preferentially inhibited hNav1.5 and hNav1.7 over the other Nav isoforms tested. While the estimated IC50values were relatively high for a PET radiotracer (8.8 µM for hNav1.5 and 142 µM for hNav1.7), this tracer provides sufficient signal-to-background ratios for PET imaging because of the high density of Nav1.7 in the sciatic nerve.
Conclusions: [18F]Radiocaine can be used to monitor injury states over time when the site of injury is known and serve as a diagnostic tool for nerve injury even in cases where the site of injury is unknown or during transitions from acute to chronic injury states. Because this radiotracer is an analogue of lidocaine, a well-tolerated local anesthetic, it has great potential for in vivo human imaging of neuropathic injuries.
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