Emergence of nociceptive functionality and opioid signaling in human induced pluripotent stem cell-derived sensory neurons.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
01 Aug 2023
01 Aug 2023
Historique:
received:
13
06
2022
accepted:
15
11
2022
medline:
17
7
2023
pubmed:
3
2
2023
entrez:
2
2
2023
Statut:
ppublish
Résumé
Induced pluripotent stem cells (iPSCs) have enabled the generation of various difficult-to-access cell types such as human nociceptors. A key challenge associated with human iPSC-derived nociceptors (hiPSCdNs) is their prolonged functional maturation. While numerous studies have addressed the expression of classic neuronal markers and ion channels in hiPSCdNs, the temporal development of key signaling cascades regulating nociceptor activity has remained largely unexplored. In this study, we used an immunocytochemical high-content imaging approach alongside electrophysiological staging to assess metabotropic and ionotropic signaling of large scale-generated hiPSCdNs across 70 days of in vitro differentiation. During this period, the resting membrane potential became more hyperpolarized, while rheobase, action potential peak amplitude, and membrane capacitance increased. After 70 days, hiPSCdNs exhibited robust physiological responses induced by GABA, pH shift, ATP, and capsaicin. Direct activation of protein kinase A type II (PKA-II) through adenylyl cyclase stimulation with forskolin resulted in PKA-II activation at all time points. Depolarization-induced activation of PKA-II emerged after 35 days of differentiation. However, effective inhibition of forskolin-induced PKA-II activation by opioid receptor agonists required 70 days of in vitro differentiation. Our results identify a pronounced time difference between early expression of functionally important ion channels and emergence of regulatory metabotropic sensitizing and desensitizing signaling only at advanced stages of in vitro cultivation, suggesting an independent regulation of ionotropic and metabotropic signaling. These data are relevant for devising future studies into the development and regulation of human nociceptor function and for defining time windows suitable for hiPSCdN-based drug discovery.
Identifiants
pubmed: 36727909
doi: 10.1097/j.pain.0000000000002860
pii: 00006396-202308000-00009
pmc: PMC10348637
doi:
Substances chimiques
Analgesics, Opioid
0
Colforsin
1F7A44V6OU
Ion Channels
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1718-1733Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.
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