Pain
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Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest human malignancies and is associated with excruciating pain, which is a serious complication and severely impacts the quality of life in patients. In human patients, poor survival prognosis is linked to remarkable remodeling of intrapancreatic nerves, which, in turn, is correlated to increased pain intensity. Understanding mechanisms underlying pain associated with PDAC has been hampered by the lack of animal models which replicate all germane aspects of the disease and importantly, enable analyses of pain associated with PDAC. ⋯ Morphological and immunohistochemical analyses revealed structural remodeling in several different types of sensory and autonomic nerve fibers. Finally, perineural invasion of tumor cells, a cardinal manifestation in human PDAC, was also observed in our orthotopic mouse model. Thus, we describe a validated tumor model for quantitatively testing hypersensitivity and pain in PDAC, which lays a crucial basis for interrogating tumor-nerve interactions and the molecular and cellular mechanisms underlying pain in PDAC.
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Classic trigeminal neuralgia (CTN) is a chronic neuropathic pain state characterized by intense, piercing spasms of the orofacial region, and may be attributable to abnormal pain processing in the central nervous system. Our study investigated neuronal alterations using voxel-based morphometry (VBM), diffuse tensor imaging (DTI), and resting-state functional connectivity in 38 patients with CTN and 38 matched healthy controls. For voxel-based morphometry analyses, patients with CTN displayed gray matter volume (GMV) reductions in the anterior-cingulate cortex (ACC) and mid-cingulate cortex, insula, secondary somatosensory cortex (S2), primary motor cortex (M1), premotor area, and several regions in the temporal lobe. ⋯ Additionally, patients with CTN had enhanced functional connectivity between the right insula/S2 and ACC, medial prefrontal cortex, posterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. Furthermore, gray matter volume of left inferior temporal gyrus negatively correlated with current pain intensity and disease duration in patients, and connectivity of the right insula/S2-ACC was negatively correlated with pain intensity, depression, and anxiety ratings. This study provides multiple lines of evidence supporting aberrant structural and functional patterns that are observed in patients with CTN, which may help us better understand the pathophysiology of CTN and facilitate the development of new therapies for this disease.
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Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. ⋯ Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity.