Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: A longitudinal MRI study

Abstract

Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague–Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7T MRI scanner 1week prior to (pre-injury) and 4 (early/subchronic) and 20weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. 1H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2weeks pre-injury, and 2, 5, 9, 14, and 19weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post-injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors.