Presynaptic Gate of Pain Control: Malfunctioning Presynaptic GABAergic Inhibition in Neuropathic and Inflammatory Pain

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dc.contributor.advisor Hu, Jing (Dr.)
dc.contributor.author Guo, Da
dc.date.accessioned 2017-08-01T08:19:56Z
dc.date.available 2017-08-01T08:19:56Z
dc.date.issued 2019-07-28
dc.identifier.other 1672097452 de_DE
dc.identifier.uri http://hdl.handle.net/10900/77304
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-773043 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-18705
dc.description.abstract GABAergic inhibition modulates nociceptive signal transmission in spinal cord via affecting both presynaptic and postsynaptic elements. Damage to nerve and/or tissue (inflammation) often disrupts this regulation and causes pathological pain. The inhibition of postsynaptic spinal neurons had been intensively studied, while the inhibition of presynaptic terminals of peripheral sensory neurons was less focused due to the technical difficulty. I generated transgenic mice, which specifically express GCaMP3, a genetically encoded calcium indicator, in nociceptors (SNS-Ai38) or all-sensory neurons (advillin-Ai38), to investigate the GABAergic presynaptic inhibition in spinal cord. GABA showed significant inhibitory effect on presynaptic nociceptor central terminals from intact mice. However, peripheral nerve injury and inflammation almost completely abolished this inhibition, mainly due to the NKCC1-dependent upregulation of intracellular [Cl-]. Moreover, inflammation could facilitate GABAergic excitatory effect, which was only observed in spinal cord from SNS-Ai38 but not from advillin-Ai38. The Nociceptorspecific and all-sensory specific GABAA receptor knockout mice (SNS-β3-/- and advillin-β3-/-) were generated to examine the function of presynaptic inhibition in vivo. Both SNS-β3-/- and advillin-β3-/- were more sensitive to thermal and mechanical stimuli compare to their wild type litter mates (β3fl/fl). Yet difference between these two conditional knockout line was observed. Inflammation could not further the mechanical allodynia in SNS-β3-/- to the same level as it did in their β3fl/fl litter mates. Such difference was not observed in advillin-β3-/- mice and their litter mates. The difference between results from SNS-Cre and advillin-Cre generated transgenic mice after inflammation most likely was caused by their different Cre recombinase expression patter in peptidergic nociceptors according to immunohistochemistry study. This implies that part of peptidergic nociceptors are crucial for inflammation induced mechanical allodynia. Overall, our data reveal that GABAergic presynaptic inhibition modulates thermal and mechanical spinal nociceptive processing. Nerve injury and peripheral inflammation can both result in nociceptor [Cl-] elevation and disturb the presynaptic regulation. Furthermore, the malfunctioning presynaptic control caused by them contributes to pain modalities differently. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification Schmerz , Chronischer Schmerz de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 570 de_DE
dc.subject.other chronic pain en
dc.subject.other dorsal root ganglion en
dc.subject.other spinal cord en
dc.subject.other presynaptic inhibition en
dc.subject.other calcium imaging en
dc.title Presynaptic Gate of Pain Control: Malfunctioning Presynaptic GABAergic Inhibition in Neuropathic and Inflammatory Pain en
dc.type Dissertation de_DE
dcterms.dateAccepted 2017-07-26
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE

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