Serotonin Plays a Key Role in the Development of Opioid-Induced Hyperalgesia in Mice.

Opioid usage for pain therapy is limited by its undesirable clinical effects, including paradoxical hyperalgesia, also known as opioid-induced hyperalgesia (OIH). However, the mechanisms associated with the development and maintenance of OIH remain unclear. Here, we investigated the effect of serotonin inhibition by the 5-HT3 receptor antagonist, ondansetron (OND), as well as serotonin deprivation via its synthesis inhibitor para-chlorophenylalanine, on mouse OIH models, with particular focus on astrocyte activation. Co-administering of OND and morphine, in combination with serotonin depletion, inhibited mechanical hyperalgesia and astrocyte activation in the spinal dorsal horn of mouse OIH models. Although previous studies have suggested that activation of astrocytes in the spinal dorsal horn is essential for the development and maintenance of OIH, herein, treatment with carbenoxolone (CBX), a gap junction inhibitor that suppresses astrocyte activation, did not ameliorate mechanical hyperalgesia in mouse OIH models. These results indicate that serotonin in the spinal dorsal horn, and activation of the 5-HT3 receptor play essential roles in OIH induced by chronic morphine, while astrocyte activation in the spinal dorsal horn serves as a secondary effect of OIH. Our findings further suggest that serotonergic regulation in the spinal dorsal horn may be a therapeutic target of OIH. PERSPECTIVE: The current study revealed that the descending serotonergic pain-facilitatory system in the spinal dorsal horn is crucial in OIH, and that activation of astrocytes is a secondary phenotype of OIH. Our study offers new therapeutic targets for OIH and may help reduce inappropriate opioid use.

Acute spatial spread of NO-mediated potentiation during hindpaw ischaemia in mice.

KEY POINTS: Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord. However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation. In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischaemia are nitric oxide (NO)-dependent and that NO is produced by ischaemia and quickly diffuses within the spinal cord. We also found that NO production induced by ischaemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase-positive dorsal horn neurons express group II mGluRs. These results suggest strongly that NO-mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain. ABSTRACT: Cortical/spinal responses to hindpaw stimulation are bilaterally potentiated by unilateral hindpaw ischaemia in mice. We tested the hypothesis that hindpaw ischaemia produces nitric oxide (NO), which diffuses in the spinal cord to induce spatially spreading potentiation. Using flavoprotein fluorescence imaging, we confirmed that the spreading potentiation in hindpaw responses was induced during ischaemia in the non-stimulated hindpaw. This spreading potentiation was blocked by spinal application of l-NAME, an inhibitor of NO synthase (NOS). Furthermore, no spreading potentiation was observed in neural NOS (nNOS) knockout mice. Spinal application of an NO donor was enough to induce cortical potentiation and mechanical hypersensitivity. The spatial distribution of NO during unilateral hindpaw ischaemia was visualized using 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM). An increase in fluorescence derived from the complex of DAF-FM with NO was observed on the ischaemic side of the spinal cord. A similar but smaller increase was also observed on the contralateral side. Somatosensory potentiation after hindpaw ischaemia is known to be inhibited by spinal application of LY354740, an agonist of group II metabotropic glutamate receptors (mGluRs). We confirmed that the spinal DAF-FM fluorescence increases during hindpaw ischaemia were not observed in the presence of LY354740. We also confirmed that approximately half of the nNOS-positive neurons in the superficial laminae of the dorsal horn expressed mGluR2 mRNA. These results suggest that disinhibition of mGluR2 produces NO which in turn induces a spreading potentiation in a wide area of the spinal cord. Such spreading, along with the consequent non-specific potentiation in the spinal cord, may trigger neuropathic pain.

CT Hounsfield Unit Is a Good Predictor of Growth in Meningiomas.

Predicting the growth rate of meningiomas is important in treatment planning. Although calcification may be an important sign of slow growth in meningiomas, the developmental process and its relation to the tumor growth pattern have not been elucidated. We retrospectively examined the location and degree of calcification in 150 meningiomas (131 asymptomatic tumors) using computed tomography (CT) scans and mean Hounsfield units (mHU). Tumor growth was evaluated using serial imaging studies wherein we calculated tumor doubling time (Td) and identified the growth curve pattern as exponential, intermediate, or decelerating. Tumors in women more frequently had calcification and showed higher mHU than those in men. The mHU was measured at least twice in 57 tumors. Tumors in women showed greater mHU increases than those in men. We found a significant correlation between Td and mHU (R = 0.49). Tumors in men and those in patients in the younger age group grew significantly faster. Multivariate analysis revealed that mHU was the only significant factor affecting Td (P <0.0001). The growth pattern was significantly related to calcification (n = 61, P = 0.0042). Tumors with decelerating growth more frequently showed calcification and had higher mHU than those with exponential growth. Receiver operating characteristic curve analysis revealed that mHU was a better predictor of growth pattern change compared with calcification on CT scan. Meningiomas with high mHU, even without calcification, were likely to show growth deceleration. Mean Hounsfield unit correlated with Td and may be a good quantitative indicator of the growth rate and pattern.

Relation extraction with weakly supervised learning based on process-structure-property-performance reciprocity.

In this study, we develop a computer-aided material design system to represent and extract knowledge related to material design from natural language texts. A machine learning model is trained on a text corpus weakly labeled by minimal annotated relationship data (~100 labeled relationships) to extract knowledge from scientific articles. The knowledge is represented by relationships between scientific concepts, such as {annealing, grain size, strength}. The extracted relationships are represented as a knowledge graph formatted according to design charts, inspired by the process-structure-property-performance (PSPP) reciprocity. The design chart provides an intuitive effect of processes on properties and prospective processes to achieve the certain desired properties. Our system semantically searches the scientific literature and provides knowledge in the form of a design chart, and we hope it contributes more efficient developments of new materials.

Diagnosis of demyelinating brain lesion simulating brain tumors on fast imaging employing steady-state acquisition magnetic resonance imaging.

BACKGROUND: A single inflammatory demyelinating brain lesion sometimes mimics a brain tumor on conventional magnetic resonance imaging (MRI), and thus poses a considerable diagnostic challenge. We assessed the usefulness of a new MRI technique, fast imaging employing steady-state acquisition (FIESTA), for the diagnosis of inflammatory demyelinating disease (IDD). METHODS: Three patients (2 males, 1 female) with a histopathologically proven inflammatory demyelinating brain lesion which mimicked a brain tumor on MRI were evaluated with a post-contrast three-dimensional FIESTA sequence before biopsy and treatment. Those images were compared with the images of intra-axial brain tumors (n = 147). RESULTS: Preoperative FIESTA showed an iso- or slightly hyperintense distinct intralesional structure that appeared reticulate or broad-line in patients with IDD. These structures traversed a hyperintense demyelinating lesion in the deep grey matter (DGM) and were connected to the surrounding extralesional area, which appeared to be dense fibers between DGM. Such distinct intralesional structures were not observed in most brain tumors. CONCLUSION: Reticulate or broad-line-like intralesional structures on FIESTA may, therefore, be suggestive of IDD rather than indicate a brain tumor.