Gamma-aminobutyric acid (GABA) is the main inhibitory/ hyperpolarizing neurotransmitter in the CNS, although it exerts important action also in the PNS. Glial Schwann cells (SC), indeed, express GABA machinery, that is GABA receptors, and are able to synthetize and release GABA, which modulates their proliferation, differentiation, myelination and likely axonal sorting. However, the participation of GABA in SC-axonal cross talk and in the peripheral neuronal firing has long been hypothesized. In this light, we recently focused our efforts on the study of GABAergic system along peripheral C-fiber axons (i.e. nociceptors), aiming to the comprehension of the physiological modulation of axonal excitability. We combined molecular biology and imaging to electrophysiological techniques in order to study the conductance of peripheral nociceptive C-fibers. In the peripheral C-fibers, acute GABA-A receptor (GABA-A) activation produced an axonal depolarization and increased excitability. Depolarizing C-fiber responses were mimicked by GABA-A agonists muscimol and gaboxadol and blocked by GABA-A antagonists bicuculline. Moreover, axonal responses to GABA were absent in mice lacking the GABA-A beta3 subunit. The magnitude and time course of GABA-A responses were coupled to the Na+/K+/Cl- cotransporter (NKCC1) activity and secondary to the Cl- ion conductance. Therefore, regulation of axonal GABA-A receptors and Cl- concentration might be an effective strategy to control C-fiber hyperexcitability in patients with chronic peripheral pain. Overall, unraveling the mechanisms of nociception under physiological conditions may provide novel findings for the comprehension of the physio-pathology of peripheral neuropathic pain. The pharmacologic opportunity to modulate the peripheral GABA-A/NKCC1 channels paves the way to alternative approaches for the treatment of neuropathic and/or chronic pain.

PERIPHERAL AXONAL TUNING BY THE GAMMA-AMINOBUTYRIC ACID TYPE A (GABA-A) RECEPTOR UNVEILS NOVEL MODULATORY MECHANISMS IN NOCICEPTION / V. Magnaghi. - In: JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM. - ISSN 1085-9489. - 28 Suppl 2:S2(2023), pp. s36-s37. [Epub ahead of print] (Intervento presentato al 13. convegno Annual Meeting of the Italian Association for the study of the Peripheral Nervous System (ASNP) tenutosi a Napoli : 25-27 maggio nel 2023).

PERIPHERAL AXONAL TUNING BY THE GAMMA-AMINOBUTYRIC ACID TYPE A (GABA-A) RECEPTOR UNVEILS NOVEL MODULATORY MECHANISMS IN NOCICEPTION

V. Magnaghi
Conceptualization
2023

Abstract

Gamma-aminobutyric acid (GABA) is the main inhibitory/ hyperpolarizing neurotransmitter in the CNS, although it exerts important action also in the PNS. Glial Schwann cells (SC), indeed, express GABA machinery, that is GABA receptors, and are able to synthetize and release GABA, which modulates their proliferation, differentiation, myelination and likely axonal sorting. However, the participation of GABA in SC-axonal cross talk and in the peripheral neuronal firing has long been hypothesized. In this light, we recently focused our efforts on the study of GABAergic system along peripheral C-fiber axons (i.e. nociceptors), aiming to the comprehension of the physiological modulation of axonal excitability. We combined molecular biology and imaging to electrophysiological techniques in order to study the conductance of peripheral nociceptive C-fibers. In the peripheral C-fibers, acute GABA-A receptor (GABA-A) activation produced an axonal depolarization and increased excitability. Depolarizing C-fiber responses were mimicked by GABA-A agonists muscimol and gaboxadol and blocked by GABA-A antagonists bicuculline. Moreover, axonal responses to GABA were absent in mice lacking the GABA-A beta3 subunit. The magnitude and time course of GABA-A responses were coupled to the Na+/K+/Cl- cotransporter (NKCC1) activity and secondary to the Cl- ion conductance. Therefore, regulation of axonal GABA-A receptors and Cl- concentration might be an effective strategy to control C-fiber hyperexcitability in patients with chronic peripheral pain. Overall, unraveling the mechanisms of nociception under physiological conditions may provide novel findings for the comprehension of the physio-pathology of peripheral neuropathic pain. The pharmacologic opportunity to modulate the peripheral GABA-A/NKCC1 channels paves the way to alternative approaches for the treatment of neuropathic and/or chronic pain.
Settore BIO/09 - Fisiologia
2023
22-mag-2023
Article (author)
File in questo prodotto:
File Dimensione Formato  
J Peripheral Nervous Sys - 2023 - - AbstractsMagnaghi.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 160.06 kB
Formato Adobe PDF
160.06 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/970917
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact