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Has Fulltext
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Keywords
- Npr2 (1)
- P2X3 (1)
- Slack (1)
- axon bifurcation (1)
- axonal pathfinding (1)
- cGKI (1)
- development (1)
- dorsal root ganglia (1)
- mice (1)
- neuropathic pain (1)
Institute
Tröster, Philip ; Haseleu, Julia ; Petersen, Jonas ; Drees, Oliver ; Schmidtko, Achim ; Schwaller, Frederick ; Lewin, Gary R. ; Ter-Avetisyan, Gohar ; Winter, York ; Peters, Stefanie ; Feil, Susanne ; Feil, Robert ; Rathjen, Fritz G. ; Schmidt, Hannes
A cGMP signaling cascade composed of C-type natriuretic peptide, the guanylyl cyclase receptor Npr2 and cGMP-dependent protein kinase I (cGKI) controls the bifurcation of sensory axons upon entering the spinal cord during embryonic development. However, the impact of axon bifurcation on sensory processing in adulthood remains poorly understood. To investigate the functional consequences of impaired axon bifurcation during adult stages we generated conditional mouse mutants of Npr2 and cGKI (Npr2fl/fl;Wnt1Cre and cGKIKO/fl;Wnt1Cre) that lack sensory axon bifurcation in the absence of additional phenotypes observed in the global knockout mice. Cholera toxin labeling in digits of the hind paw demonstrated an altered shape of sensory neuron termination fields in the spinal cord of conditional Npr2 mouse mutants. Behavioral testing of both sexes indicated that noxious heat sensation and nociception induced by chemical irritants are impaired in the mutants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are not affected. Recordings from C-fiber nociceptors in the hind limb skin showed that Npr2 function was not required to maintain normal heat sensitivity of peripheral nociceptors. Thus, the altered behavioral responses to noxious heat found in Npr2fl/fl;Wnt1Cre mice is not due to an impaired C-fiber function. Overall, these data point to a critical role of axonal bifurcation for the processing of pain induced by heat or chemical stimuli.
Viele Studien konnten in den letzten Jahren aufzeigen, dass Stickstoffmonoxid (NO)/cGMP-Signaling eine wichtige Rolle in der Verarbeitung chronischer Schmerzprozesse einnimmt. Bei Verletzung peripherer Nerven oder Entzündung im Gewebe wird NO gebildet, das durch Stimulation der NO-sensitiven Guanylatzyklase (NO-GC) die cGMP-Bildung katalysiert. Seit einigen Jahren ist bekannt, dass zwei Isoformen dieses Enzyms existieren, NO-GC1 und NO-GC2. Das Expressionsmuster der beiden Isoformen im nozizeptiven System und der jeweilige Einfluss auf die Schmerzverarbeitung ist jedoch bisher völlig unbekannt. In dieser Arbeit wurde die Expression der NO-GC1 und NO-GC2 in den Spinalganglien (DRGs) und im Rückenmark von Mäusen charakterisiert und das Verhalten von NO-GC1 und NO-GC2 Knockout (KO)-Mäusen in verschiedenen Schmerzmodellen untersucht. Mit Immunfluoreszenzfärbungen und In-situ-Hybridisierungen wurde in dieser Arbeit dargestellt, dass die zwei Isoformen in Interneuronen des Rückenmarks lokalisiert sind, wobei die NO-GC1 vorwiegend in inhibitorischen Interneuronen exprimiert wird. In den DRGs konnte die Expression in nicht-neuronalen Zellen nachgewiesen werden, wobei nur die NO-GC2 in Satellitenzellen detektiert werden konnte. Die NO-GC1 KO-Mäuse zeigten eine verringerte mechanische Hypersensitivität in neuropathischen Schmerzmodellen, aber ein normales Verhalten in Modellen inflammatorischer Schmerzen. Im Gegensatz zu diesen Ergebnissen zeigten die NO-GC2 KO-Mäuse ein erhöhtes Schmerzverhalten in Entzündungsmodellen, aber kein verändertes Verhalten in Modellen neuropathischer Schmerzen. Die gezielte Deletion der NO-GC1 und NO-GC2 in Interneuronen des Rückenmarks führte in den entsprechenden Tieren zu Verhaltensänderungen in der Schmerzwahrnehmung, die den Phänotypen der globalen NO-GC KO-Tieren in Schmerzmodellen ähnelte. Zusammengefasst zeigen die Daten dieser Arbeit, dass die NO-GC1- oder NO-GC2-vermittelte cGMP-Produktion in Interneuronen des Rückenmarks sehr wichtige, und teilweise gegensätzliche Funktionen bei der Verarbeitung chronischer Schmerzsignale einnimmt.
Functional coupling of Slack channels and P2X3 receptors contributes to neuropathic pain processing
(2021)
Lu, Ruirui ; Metzner, Katharina ; Zhou, Fangyuan ; Flauaus, Cathrin ; Balzulat, Annika ; Engel, Patrick ; Petersen, Jonas ; Ehinger, Rebekka ; Bausch, Anne ; Ruth, Peter ; Lukowski, Robert ; Schmidtko, Achim
The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated IKNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated IKNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.
Acharya, Shreyasi ; Adamová, Dagmar ; Agarwal, Apar ; Aglieri Rinella, Gianluca ; Aglietta, Luca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Shakeel ; Ahn, Sang Un ; Ahuja, Ishaan ; Akindinov, Alexander ; Akishina, Valentina ; Al-Turany, Mohammad ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfanda, Haidar Mas’ud ; Alfaro Molina, Jose Ruben ; Ali, Bushra ; Alici, Andrea ; Alizadehvandchali, Negin ; Alkin, Anton ; Alme, Johan ; Alocco, Giacomo ; Alt, Torsten ; Altamura, Anna Rita ; Altsybeev, Igor ; Alvarado Garcia, Jesús Ricardo ; Anaam, Mustafa Naji ; Andrei, Cristian ; Andreou, Nicodemos ; Andronic, Anton ; Andronov, Evgeny ; Anguelov, Venelin ; Antinori, Federico ; Antonioli, Pietro ; Apadula, Nicole ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arata, Carolina ; Arcelli, Silvia ; Aresti, Mauro ; Arnaldi, Roberta ; Arneiro, Jhoao Gabriel Martins Campos Almeida ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Augustinus, Andre ; Averbeck, Ralf Peter ; Azmi, Mohd Danish ; Baba, Hitoshi ; Badalà, Angela ; Bae, Joonsuk ; Baek, Yong Wook ; Bai, Xiaozhi ; Bailhache, Raphaëlle ; Bailung, Yoshini ; Bala, Renu ; Balbino, Alessandro ; Baldisseri, Alberto ; Balis, Bartosz ; Banerjee, Debjani ; Banoo, Zarina ; Barbasova, Veronika ; Barile, Francesco ; Barioglio, Luca ; Barlou, Maria ; Barman, Banajit ; Barnaföldi, Gergely Gábor ; Barnby, Lee Stuart ; Barreau, Emilie Martine ; Ramillien Barret, Valerie ; Barreto De Oliveira Campos, Leonardo ; Bartels, Clara ; Barth, Klaus ; Bartsch, Esther ; Bastid, Nicole ; Basu, Sumit ; Batigne, Guillaume ; Battistini, Daniel ; Batyunya, Boris ; Bauri, Dibakar ; Bazo Alba, José Luis ; Bearden, Ian Gardner ; Beattie, Caitlin ; Becht, Pascal ; Behera, Debadatta ; Belikov, Iouri ; Bell Hechavarria, Ailec de la Caridad ; Bellini, Francesca ; Bellwied, Rene ; Belokurova, Svetlana ; Espinoza Beltran, Lucina Gabriela ; Vasquez Beltran, Yael Antonio ; Bencédi, Gyula ; Bensaoula, Adel ; Beolè, Stefania ; Berdnikov, Yaroslav ; Berdnikova, Anastasia ; Bergmann, Luisa ; Besoiu, Mihaela Gabriela ; Betev, Latchezar ; Bhaduri, Partha Pratim ; Bhasin, Anju ; Bhat, Mohammad Asif ; Bhattacharjee, Buddhadeb ; Bianchi, Livio ; Bianchi, Nicola ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bigot, Alexandre Patrick ; Bilandzic, Ante ; Biro, Gabor ; Biswas, Saikat ; Bize, Nicolas Luc ; Blair, Justin Thomas ; Blau, Dmitry S. ; Blidaru, Mihail-Bogdan ; Bluhme, Nora ; Blume, Christoph ; Boca, Gianluigi ; Bock, Friederike ; Bodova, Tea ; Bok, Jeongsu ; Boldizsar, Laszlo ; Bombara, Marek ; Bond, Peter Matthew ; Bonomi, Germano ; Borel, Herve ; Borissov, Alexander ; Borquez Carcamo, Andres Gerardo ; Bossi, Hannah ; Botta, Elena ; El Mard Bouziani, Youssef ; Bratrud, Lars ; Braun-Munzinger, Peter ; Bregant, Marco ; Broz, Michal ; Bruno, Giuseppe Eugenio ; Buckland, Matthew Daniel ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bühler, Paul ; Burmasov, Nazar ; Buthelezi, Edith Zinhle ; Bylinkin, Alexander ; Bysiak, Sebastian Adam ; 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The intense photon fluxes from relativistic nuclei provide an opportunity to study photonuclear interactions in ultraperipheral collisions. The measurement of coherently photoproduced π+π−π+π− final states in ultraperipheral Pb-Pb collisions at sNN−−−√=5.02 TeV is presented for the first time. The cross section, dσ/dy, times the branching ratio (ρ→π+π+π−π−) is found to be 47.8±2.3 (stat.)±7.7 (syst.) mb in the rapidity interval |y|<0.5. The invariant mass distribution is not well described with a single Breit-Wigner resonance. The production of two interfering resonances, ρ(1450) and ρ(1700), provides a good description of the data. The values of the masses (m) and widths (Γ) of the resonances extracted from the fit are m1=1385±14 (stat.)±3 (syst.) MeV/c2, Γ1=431±36 (stat.)±82 (syst.) MeV/c2, m2=1663±13 (stat.)±22 (syst.) MeV/c2 and Γ2=357±31 (stat.)±49 (syst.) MeV/c2, respectively. The measured cross sections times the branching ratios are compared to recent theoretical predictions.
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