Oral manganese as an MRI contrast agent for the detection of nociceptive activity

Abstract

The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.

Neuropathic Pain Mechanisms and Imaging

“…(Bottom row) Three-dimensional (3D) maximum intensity projection (MIP) of lumbosacral spinal cord and plexus in the same SNI and control rats. Increased color intensity of the lumbar plexus is noted compared with control, suggesting increased calcium influx in the pain model (Jacobs et al 54 ). (b) 3D MIP of lumbosacral spinal cord and plexus precontrast (baseline), and after intraperitoneal manganese injection in a model of CCI of the sciatic nerve and an uninjured control rat.…”

MRI contrast agents: Classification and application (Review)

“…Air and clay are used to reduce the T2 signal intensity (25,26). Gadolinium-based agents, SPIO, manganese-containing agents and barium sulfate suspensions have been studied as oral MRI contrast agents (27,28). The oral administration of MRI contrast agents containing manganese is a novel, noninvasive method for imaging (27).…”

“…Gadolinium-based agents, SPIO, manganese-containing agents and barium sulfate suspensions have been studied as oral MRI contrast agents (27,28). The oral administration of MRI contrast agents containing manganese is a novel, noninvasive method for imaging (27). Barium sulfate suspensions are useful as negative oral MRI contrast agents (28).…”

Molecular Imaging: An Innovative Force in Musculoskeletal Radiology

“…In a preclinical study using orally administered manganese, manganese-enhanced MRI highlighted the lumbar plexus of a sciatic nerve injury model. T1-weighted signal-to-noise ratios in sciatic nerves within the pelvis correlated well with manganese content in the nerves measured by inductively coupled plasma spectrometry [98]. Control uninjured animals showed significantly less T1-weighted manganese-enhanced MRI signal than did the neuropathic pain models, which correlated with behavior scores and lower manganese content as measured by inductively coupled plasma spectrometry.…”