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

DSpace Repository


Dateien:
Aufrufstatistik

URI: http://hdl.handle.net/10900/77304
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-773043
http://dx.doi.org/10.15496/publikation-18705
Dokumentart: Dissertation
Date: 2019-07-28
Language: English
Faculty: 8 Zentrale, interfakultäre und fakultätsübergreifende Einrichtungen
Department: Biologie
Advisor: Hu, Jing (Dr.)
Day of Oral Examination: 2017-07-26
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
Keywords: Schmerz , Chronischer Schmerz
Other Keywords:
chronic pain
dorsal root ganglion
spinal cord
presynaptic inhibition
calcium imaging
License: Publishing license including print on demand
Order a printed copy: Print-on-Demand
Show full item record

Inhaltszusammenfassung:

Dissertation ist gesperrt bis 28.07.2019 !

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.

This item appears in the following Collection(s)