Mol Pain
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Can mice recognize themselves in a mirror? The answer is unclear. Previous studies have reported that adult mice - when shown itch-like videos - demonstrated itch empathy. However, this was proven to be unreproducible in other studies. ⋯ Differently, in the case of chemical pain (formalin injection), animals' nociceptive responses to formalin during Phase II were significantly enhanced in the mirrored open field. A new format of heat map was developed to help the analysis of the trace of mice in the open field. Our results suggest that mice do recognize the presence of mice in the mirror, and their nociceptive - but not itch - responses are enhanced.
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Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. ⋯ Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.
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Randomized Controlled Trial
Human safety study of a selective neuronal adenylate cyclase 1 (AC1) inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice.
Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. ⋯ Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.
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Prolongation of postsurgical pain caused by pre-operative stress is a clinically significant problem, although the mechanisms are not fully understood. Stress can promote the pro-inflammatory activation of microglia, and the transcription factor CCAAT/enhancer-binding protein (C/EBP) β regulates pro-inflammatory gene expression in microglia. Therefore, we speculated that C/EBPβ in spinal microglia may have critical roles in the development of chronic postsurgical pain. ⋯ Subsequently, microinjection of C/EBPβ siRNA attenuated the duration of SPS-prolonged postoperative mechanical allodynia and inhibited microglial activation in the spinal cord. Conversely, mimicking this increase in C/EBPβ promoted microglial activation via pretreatment with a pre-injection of AAV5-C/EBPβ, leading to prolongation of postsurgical pain. Overall, these results suggested that spinal microglia may play key roles in prolongation of postsurgical pain induced by pre-operative stress and that C/EBPβ may be a potential target for disease treatment.
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Abnormal pain has recently been estimated to affect ∼50 million adults each year within the United States. With many treatment options for abnormal pain, such as opioid analgesics, carrying numerous deleterious side effects, research into safer and more effective treatment options is crucial. To help elucidate the mechanisms controlling nociceptive sensitivity, the Drosophila melanogaster larval nociception model has been used to characterize well-conserved pathways through the use of genetic modification and/or injury to alter the sensitivity of experimental animals. ⋯ Underexpression of Armadillo resulted in hyposensitivity, while overexpression of wild-type Armadillo or expression of a degradation-resistant Armadillo resulted in hypersensitivity. Neither underexpression nor overexpression of Armadillo resulted in observed dendritic morphological changes that could contribute to behavioral phenotypes observed. These results showed that focused manipulation of Armadillo expression within the nociceptors is sufficient to modulate baseline response in the nociceptors to a noxious stimulus and that these changes are not shown to be associated with a morphogenetic effect.