Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.
Introduction: The presently used impulse echo ultrasound examination is not suitable to provide relevant and reliable information about the jawbone, because ultrasound (US) almost completely reflects from the hard cortical jawbone. At the same time, "focal osteoporotic bone marrow defects" (BoneMarrowDefects = BMD) in jawbone are the subject of scientific presentations and discussions. Purpose: Can a newly developed trans-alveolar ultrasonic sonography (TAU-n) device locate and ascertain BMD? Patients and Methods: TAU-n consists of a two-part handpiece with an extraoral ultrasound transmitter and an intraoral ultrasound receiver. The TAU-n computer display shows the different jawbone densities with corresponding colour coding. The changes in jawbone density are also displayed numerically. The validation of TAU-n readings: A usual orthopantomogram (2D-OPG) on its own is not suitable for unequivocally determining jawbone density and has to be excluded from this validation. For validation, a 3D-digital volume tomogram/cone beam computer tomogram (DVT/CBCT) with the capacity to measure Hounsfield units (HU) and a TAU-n are used to determine the presence of preoperative BMD in 82 patient cases. Postoperatively, histology samples and multiplex analysis of RANTES/CCL5 (R/C) expression derived from surgically cleaned BMD areas are evaluated. Results: In all 82 bone samples, DVT-HU, TAU-n values and R/C expressions show the presence of BMD with chronic inflammatory character. However, five histology samples showed no evidence of BMD. All four evaluation criteria (DVT-HU, TAU-n, R/C, histology) confirm the presence of BMD in each of the 82 samples. Conclusion: The TAU-n method almost completely matches the diagnostic reliability of the other methods. The newly developed TAU-n scanner is a reliable and radiation-free option to detect BMD.
Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.
Background Cytokines, especially chemokines, are of increasing interest in immunology. This study characterizes the little-known phenomenon of “bone marrow defects of the jawbone” (BMDJ) with known overexpression of the chemokine RANTES/CCL5 (R/C). Purpose Our investigation clarifies why BMDJ and the intensity of local R/C overexpression are challenging to detect, as examined in patients with seven different systemic immunological diseases. Specifically, we investigate whether R/C overexpression is specific to certain disease groups or if it represents a type of signal disruption found in all systemic immunological diseases. Patients and Methods In a total of 301 patients, BMDJ was surgically repaired during clinical practice to reduce “silent inflammation” associated with the presence of jaw-related pathologies. In each case of BMDJ, bone density was measured preoperatively (in Hounsfield units [HU]), while R/C expression was measured postoperatively. Each of the 301 patients suffered from allergies, atypical facial and trigeminal pain, or were diagnosed with neurodegenerative diseases, tumors, rheumatism, chronic fatigue syndrome, or parasympathetic disorders. Results In all BMDJ cases, strongly negative HU values indicated decreased bone density or osteolysis. Consistently, all cases of BMDJ showed elevated R/C expression. These findings were consistently observed in every disease group. Discussion BMDJ was confirmed in all patients, as verified by the HU measurements and laboratory results related to R/C expression. The hypothesis that a specific subset of the seven disease groups could be distinguished either based on the increased presence of BMDJ and by the overexpression of R/C could not be confirmed. A brief literature review confirms the importance of R/C in the etiology of each of the seven disease groups. Conclusion In this research, the crucial role played by BMDJ and the chemokine R/C in inflammatory and immune diseases is discussed for seven groups of patients. Each specific immune disease can be influenced or propelled by BMDJ-derived R/C inflammatory signaling pathways.
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