The contribution of endocytosis to sensitization of nociceptors and synaptic transmission in nociceptive circuits.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
01 06 2023
01 06 2023
Historique:
received:
23
06
2022
accepted:
08
11
2022
pmc-release:
01
06
2024
medline:
15
5
2023
pubmed:
16
11
2022
entrez:
15
11
2022
Statut:
ppublish
Résumé
Chronic pain involves sensitization of nociceptors and synaptic transmission of painful signals in nociceptive circuits in the dorsal horn of the spinal cord. We investigated the contribution of clathrin-dependent endocytosis to sensitization of nociceptors by G protein-coupled receptors (GPCRs) and to synaptic transmission in spinal nociceptive circuits. We determined whether therapeutic targeting of endocytosis could ameliorate pain. mRNA encoding dynamin (Dnm) 1 to 3 and adaptor-associated protein kinase 1 (AAK1), which mediate clathrin-dependent endocytosis, were localized to primary sensory neurons of dorsal root ganglia of mouse and human and to spinal neurons in the dorsal horn of the mouse spinal cord by RNAScope. When injected intrathecally to mice, Dnm and AAK1 siRNA or shRNA knocked down Dnm and AAK1 mRNA in dorsal root ganglia neurons, reversed mechanical and thermal allodynia and hyperalgesia, and normalized nonevoked behavior in preclinical models of inflammatory and neuropathic pain. Intrathecally administered inhibitors of clathrin, Dnm, and AAK1 also reversed allodynia and hyperalgesia. Disruption of clathrin, Dnm, and AAK1 did not affect normal motor functions of behaviors. Patch clamp recordings of dorsal horn neurons revealed that Dnm1 and AAK1 disruption inhibited synaptic transmission between primary sensory neurons and neurons in lamina I/II of the spinal cord dorsal horn by suppressing release of synaptic vesicles from presynaptic primary afferent neurons. Patch clamp recordings from dorsal root ganglion nociceptors indicated that Dnm siRNA prevented sustained GPCR-mediated sensitization of nociceptors. By disrupting synaptic transmission in the spinal cord and blunting sensitization of nociceptors, endocytosis inhibitors offer a therapeutic approach for pain treatment.
Identifiants
pubmed: 36378744
doi: 10.1097/j.pain.0000000000002826
pii: 00006396-202306000-00016
pmc: PMC10182228
mid: NIHMS1849655
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1355-1374Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE026806
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE029951
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118971
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102722
Pays : United States
Informations de copyright
Copyright © 2022 International Association for the Study of Pain.
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