Manganese-enhanced MRI reveals changes within brain anxiety and aversion circuitry in rats with chronic neuropathic pain- and anxiety-like behaviors

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2020-12, Vol.223, p.117343-117343, Article 117343
• Main Authors: McIlwrath, Sabrina L., Montera, Marena A., Gott, Katherine M., Yang, Yirong, Wilson, Colin M., Selwyn, Reed, Westlund, Karin N.
• Format: Article
• Language: English
• Subjects: Amygdala; Animal models; Animals; Anxiety; Anxiety - etiology; Anxiety - physiopathology; Aversion; Behavior; Brain; Brain - physiopathology; Brain mapping; Brain Mapping - methods; CCI-ION; Chronic pain; Clinical trials; Contrast Media; Depression; Functional magnetic resonance imaging; Gliosis; Habenula; Hypersensitivity; Laboratory animals; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Manganese; Neural Pathways - physiopathology; Neuralgia; Neuralgia - complications; Neuralgia - physiopathology; Neuroimaging; Neuropathic pain; Opioids; Orofacial pain; Pain; Pain matrix; Patients; Periaqueductal gray area; Rats, Sprague-Dawley; Reinforcement; Somatosensory cortex; Substantia grisea; Surgery; Thalamus; Trigeminal nerve; Water content
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2020.117343

•Chronic hypersensitivity induces anxiety-like behavior in the rodent chronic CCI-ION trigeminal neuropathic pain model.•MEMRI T1 signal intensity increase in anterior cingulate gyrus (ACC), amygdala, dentate gyrus, and habenula indicates neural activity in emotional brain regions activated by chronic pain. Reduced signal intensity in primary somatosensory cortex and dorsal raphe suggest potential inhibitory system modulation at those sites.•MEMRI T2 signal intensity increase in ACC, thalamus, habenula is an indication of tissue water content, cell dysfunction and/or reactive astrogliosis, but reduced T2 signal intensity in dorsal raphe nucleus, ventrolateral PAG, and primary somatosensory cortex in animals with chronic orofacial pain indicates dysregulated function.•MEMRI T1 and T2 signal intensity increases suggest over-activation in both pain-related anxiety and aversion circuitry can be monitored in chronic neuropathic pain models and is relevant to preclinical therapeutic testing. Chronic pain often predicts the onset of psychological distress. Symptoms including anxiety and depression after pain chronification reportedly are caused by brain remodeling/recruitment of the limbic and reward/aversion circuitries. Pain is the primary precipitating factor that has caused opioid overprescribing and continued overuse of opioids leading to the current opioid epidemic. Yet experimental pain therapies often fail in clinical trials. Better understanding of underlying pathologies contributing to pain chronification is needed to address these chronic pain related issues. In the present study, a chronic neuropathic pain model persisting 10 weeks was studied. The model develops both anxiety- and pain-related behavioral measures to mimic clinical pain. The manganese-enhanced magnetic resonance imaging (MEMRI) utilized improved MRI signal contrast in brain regions with higher neuronal activity in the rodent chronic constriction trigeminal nerve injury (CCI-ION) model. T1-weighted MEMRI signal intensity was increased compared to controls in supraspinal regions of the anxiety and aversion circuitry, including anterior cingulate gyrus (ACC), amygdala, habenula, caudate, ventrolateral and dorsomedial periaqueductal gray (PAG). Despite continuing mechanical hypersensitivity, MEMRI T1 signal intensity as the neuronal activity measure, was not significantly different in thalamus and decreased in somatosensory cortex (S1BF) of CCI-ION rats compared to naïve controls. This is