Bilateral peripheral neural activity observed in vivo following unilateral nerve injury

Abstract

Manganese-enhanced magnetic resonance imaging (MRI) is a surrogate method to measure calcium content in nervous system since manganese physiologically follows calcium. Manganese is detectable in MRI and therefore visualizes structures and cell populations that actively regulate calcium. Since calcium is actively recruited for the transmission of action potentials, our purpose is to validate manganese-enhanced MRI for detection of changes in lumbar nerves related to nociception. A neuropathic pain model was created by chronic constrictive injury of the left sciatic nerve of Sprague-Dawley rats. Behavioral measurements, using von Frey's tests, confirmed the presence of significant allodynia in the left hind limb of animals in the injured group. T1-weighted fast spin echo images were obtained of the lumbar cord and plexus of animals with injured left sciatic nerve and uninjured animals (control) scanned in a 7 Tesla magnet after intraperitoneal manganese chloride administration four weeks after surgery. Lumbar nerve roots and sciatic nerves in the injured group show increased normalized manganese-enhanced MRI signal, representing manganese enhancement, compared to the control group. In conclusion, animals with neuropathic pain in the left hind limb show increased manganese uptake in not only the injured sciatic nerve but also in the contralateral uninjured sciatic nerve on manganese-enhanced MRI in vivo. Although poorly understood, this finding corroborates ex vivo finding of bilateral nociceptive-related molecular changes in the nervous system of unilateral pain models.

Keywords: Manganese-enhanced magnetic resonance imaging; animal model; chronic constrictive injury; neuropathic pain; sciatic nerve injury.

Figure 1

Placement of ROIs around sciatic nerves. Axial T1 weighted MRI slice of the posterior rat pelvis (inset image of entire transaxial slice shown in upper right corner) showing sacrum (multiple small arrows), right and left sciatic nerves, representative regions-of-interest (ROI) around the left sciatic nerve and muscle. Inset shows the entire slice from which the magnified slice was obtained.

Figure 2

Measurements of allodynia. Von Frey’s test shows increased sensitivity to mechanical stimulation in the operated paw (left) in the CCI group as evidenced by a reduction in the paw withdrawal threshold compared to the non-operated paw (right) or either paws in the control group (***p<0.002).

Figure 3

Normalized MEMRI signal in sciatic nerves. Average normalized MEMRI signal (± s.e.m) in peripheral nerves is increased in response to Chronic Constrictive Injury (CCI) (***p<0.01).

Figure 4

Transaxial images of a representative baseline scan, and representative MEMRI scans from each group showing the sciatic nerves in the pelvis anterior to the sacrum. The top row shows the entire slice while the bottom row zooms into the relevant part as marked by boxes in the top row. All images are similarly windowed. MEMRI improves the signal in both groups over baseline. In MEMRI, the CCI animal shows higher signal intensity in the sciatic nerve than the control animal. The higher signal relative to the surrounding muscle makes the nerves more visible in the CCI MEMRI.

Figure 5

Reconstructed MEMRI views of the lumbar plexus. Normalized 3D maximum intensity projection (MIP) images (posterior projection) of a representative baseline scan, and representative MEMRI scans from each group showing the lumbar spinal cord, cauda equina and lumbar plexus. MEMRI improves the signal in both groups over baseline. In MEMRI, the CCI animal shows higher signal intensity in the peripheral nerves of the lumbar plexus than the control animal.