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Chemogenetic activation of astrocytes promotes remyelination and restores cognitive deficits in visceral hypersensitive rats.

Using a well-established chronic visceral hypersensitivity (VH) rat model, we characterized the decrease of myelin basic protein, reduced number of mature oligodendrocytes (OLs), and hypomyelination in the anterior cingulate cortex (ACC). The results of rat gambling test showed impaired decision-making, and the results of electrophysiological studies showed desynchronization in the ACC to basolateral amygdala (BLA) neural circuitry. Astrocytes release various factors that modulate oligodendrocyte progenitor cell proliferation and myelination. Astrocytic Gq-modulation through expression of hM3Dq facilitated oligodendrocyte progenitor cell proliferation and OL differentiation, and enhanced ACC myelination in VH rats. Activating astrocytic Gq rescued impaired decision-making and desynchronization in ACC-BLA. These data indicate that ACC hypomyelination is an important component of impaired decision-making and network desynchronization in VH. Astrocytic Gq activity plays a significant role in oligodendrocyte myelination and decision-making behavior in VH. Insights from these studies have potential for interventions in myelin-related diseases such as chronic pain-associated cognitive disorders.

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Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands.

The discovery of efficacious and safe analgesics with reduced side effects is the foremost challenge in the pain field. In this work, we report the and evaluation of linear and cyclic analogues of biphalin with the aim to complete the series of structural modifications previously applied in the development of opioid peptides incorporating a xylene bridge. Replacement of Tyr by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue and cyclic analogue resulted in two new compounds (namely, and ) endowed with improved KOR/MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, , was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.

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N-adamantyl-anthranil amide derivatives: New selective ligands for the cannabinoid receptor subtype 2 (CB2R).

Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N-adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade.

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Microglial Depletion does not Affect the Laterality of Mechanical Allodynia in Mice.

Mechanical allodynia (MA), including punctate and dynamic forms, is a common and debilitating symptom suffered by millions of chronic pain patients. Some peripheral injuries result in the development of bilateral MA, while most injuries usually led to unilateral MA. To date, the control of such laterality remains poorly understood. Here, to study the role of microglia in the control of MA laterality, we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice. Surprisingly, the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA. Moreover, in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons. Consistent with behavioral results, microglial depletion did not prevent the opening of bilateral gates for Aβ pathways in the superficial dorsal horn. This study challenges the role of microglia in the control of MA laterality in mice. Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.

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Adolescent chronic pain links parental rejection to young adult biopsychosocial problems.

Little is known about the mediating role of adolescent chronic pain in the connection between adolescent parental rejection and psychosocial and physical health (i.e., disease risk) outcomes in young adulthood (YA). To address this gap, the present study tested a model of a successively contingent developmental process that integrates neurophysiological research and the life course developmental perspective. The model included parental rejection and chronic pain in adolescence and depressive symptoms, low education attainment, economic hardship and allostatic load in YA. The study utilized 13 years of prospective data from a nationally representative sample of 11,030 US adolescents. The findings largely supported the hypothesized model. Adolescent chronic pain, as influenced by parental rejection, was associated with depressive symptoms and economic hardship in YA. In addition, parental rejection directly influenced depressive symptoms, education level and economic hardship, all of which, in turn, contributed to greater physical health risk (i.e., allostatic load) in YA. These associations persisted even after controlling for adolescent illness, depressive symptoms, age, sex and race/ethnicity. Multi-group analysis showed that female participants were more vulnerable to stressful parental rejection and socioeconomic difficulties in YA. The theoretical and practical implications of these findings are discussed.

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Migraine and its association with pubertal maturation and behavioral traits among adolescent girls.

To determine if the ages at pubertal milestones are associated with the prevalence of adolescent migraine.

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SCN9A variant in a family of mixed breed dogs with congenital insensitivity to pain.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSANs) are a rare group of genetic disorders causing inability to feel pain. Three different associated variants have been identified in dogs: 1 in Border Collies, 1 in mixed breed dogs, and 1 in Spaniels and Pointers.

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Penalized optimal scaling for ordinal variables with an application to international classification of functioning core sets.

Ordinal data occur frequently in the social sciences. When applying principal component analysis (PCA), however, those data are often treated as numeric, implying linear relationships between the variables at hand; alternatively, non-linear PCA is applied where the obtained quantifications are sometimes hard to interpret. Non-linear PCA for categorical data, also called optimal scoring/scaling, constructs new variables by assigning numerical values to categories such that the proportion of variance in those new variables that is explained by a predefined number of principal components (PCs) is maximized. We propose a penalized version of non-linear PCA for ordinal variables that is a smoothed intermediate between standard PCA on category labels and non-linear PCA as used so far. The new approach is by no means limited to monotonic effects and offers both better interpretability of the non-linear transformation of the category labels and better performance on validation data than unpenalized non-linear PCA and/or standard linear PCA. In particular, an application of penalized optimal scaling to ordinal data as given with the International Classification of Functioning, Disability and Health (ICF) is provided.

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Human-specific duplicate CHRFAM7A gene is associated with more severe osteoarthritis and amplifies pain behaviours.

CHRFAM7A is a uniquely human fusion gene that functions as a dominant negative regulator of alpha 7 acetylcholine nicotinic receptor (α7nAChR) in vitro. This study determined the impact of CHRFAM7A on α7nAChR agonist responses, osteoarthritis (OA) severity and pain behaviours and investigated mechanisms.

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Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance.

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.

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