Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats
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Manganese‑enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats Myeounghoon Cha1* , Songyeon Choi1,2, Kyeongmin Kim1,2 and Bae Hwan Lee1,2*
Abstract Neuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats. Keywords: MEMRI, mTOR, Chronic pain, Torin1, XL388 Introduction Neuropathic pain arises from an initial injury, such as neuropathy caused by a lesion of or damage to the somatosensory nervous system, that can lead to chronic pain [1]. While identifying brain abnormalities underlying chronic pain sensation could be a first step in clinical treatment, investigation of changes in cerebral neuronal activity is a challenge for functional imaging. Nevertheless, current manganese-enhanced magnetic resonance imaging (MEMRI) tools have provided a viable method for visualizing cortical responses after evoked and/ or spontaneous pain [2, 3]. The chemical properties of *Correspondence: [email protected]; [email protected] 1 Department of Physiology, Yonsei University College of Medicine, 50‑1, Yonsei‑ro, Seodaemun‑gu, 03722 Seoul, Republic of Korea Full list of author information is available at the end of the article
Mn2+ resemble those of Ca2+, and Mn2+ acts as a paramagnetic neuronal tract tracer, as its transport uses voltage-gated Ca2+ channels throughout the nervous system [4–6]. Experimental hyperalgesia produces the upregulated neuronal activation of brain responses within pain-processing regions, including the anterior cingulate cortex (ACC), insular cortex (IC), and primary (SI) and secondary somatosensory cor
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