Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: A new window to study experimental spontaneous pain?

• Published in: NeuroImage (Orlando, Fla.) Vol. 157; pp. 500 - 510
• Main Authors: Devonshire, I.M., Burston, J.J., Xu, L., Lillywhite, A., Prior, M.J., Watson, D.J.G., Greenspon, C.M., Iwabuchi, S.J., Auer, D.P., Chapman, V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2017; Elsevier Limited; Academic Press; Elsevier
• Subjects: Acute Pain - diagnostic imaging; Acute Pain - physiopathology; Amygdala; Anesthesia; Animal models; Animals; Artefacts; Arthralgia - diagnostic imaging; Arthralgia - physiopathology; Asymmetry; Behavior, Animal - physiology; Brain; Cerebrum - diagnostic imaging; Cerebrum - physiopathology; Chondrocytes; Chronic pain; Chronic Pain - diagnostic imaging; Chronic Pain - physiopathology; Cortex (motor); Data processing; Disease Models, Animal; fMRI; Growth factors; Hyperalgesia; Image Enhancement - methods; Injection; Isoflurane; Knee; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Manganese; Nerve growth factor; Neuroimaging; NMR; Nociception; Nuclear magnetic resonance; On-going pain; Osteoarthritis; Pain; Pain perception; Rats; Rats, Sprague-Dawley; Resonance; Rodents; Weight reduction; Wheel running; Nociception; fMRI; On-going pain; Osteoarthritis; Manganese
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2017.06.034

Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats. •Imaging of animal models of pain often focuses on evoked rather than on-going pain.•We tested whether such on-going pain could be detected with manganese-enhanced MRI.•Robust behavioural measures of pain were found in our rat models of knee-joint pain.•Behavioural measures were correlated with MR intensity in several key brain regions.•Manganese-enhanced MRI could be useful in studying neural bases of spontaneous pain.