A Selective Adenylyl Cyclase 1 Inhibitor Relieves Pain Without Causing Tolerance.
AC1
adenylyl cyclase
analgesia
pain
tolerance
Journal
Frontiers in pharmacology
ISSN: 1663-9812
Titre abrégé: Front Pharmacol
Pays: Switzerland
ID NLM: 101548923
Informations de publication
Date de publication:
2022
2022
Historique:
received:
04
05
2022
accepted:
20
06
2022
entrez:
28
7
2022
pubmed:
29
7
2022
medline:
29
7
2022
Statut:
epublish
Résumé
Among the ten different adenylyl cyclase isoforms, studies with knockout animals indicate that inhibition of AC1 can relieve pain and reduce behaviors linked to opioid dependence. We previously identified ST034307 as a selective inhibitor of AC1. The development of an AC1-selective inhibitor now provides the opportunity to further study the therapeutic potential of inhibiting this protein in pre-clinical animal models of pain and related adverse reactions. In the present study we have shown that ST034307 relives pain in mouse models of formalin-induced inflammatory pain, acid-induced visceral pain, and acid-depressed nesting. In addition, ST034307 did not cause analgesic tolerance after chronic dosing. We were unable to detect ST034307 in mouse brain following subcutaneous injections but showed a significant reduction in cAMP concentration in dorsal root ganglia of the animals. Considering the unprecedented selectivity of ST034307, we also report the predicted molecular interaction between ST034307 and AC1. Our results indicate that AC1 inhibitors represent a promising new class of analgesic agents that treat pain and do not result in tolerance or cause disruption of normal behavior in mice. In addition, we outline a unique binding site for ST034307 at the interface of the enzyme's catalytic domain.
Identifiants
pubmed: 35899113
doi: 10.3389/fphar.2022.935588
pii: 935588
pmc: PMC9310748
doi:
Types de publication
Journal Article
Langues
eng
Pagination
935588Informations de copyright
Copyright © 2022 Giacoletti, Price, Hoelz, Shremo Msdi, Cossin, Vazquez-Falto, Amorim Fernandes, Santos de Pontes, Wang, Boechat, Nornoo and Brust.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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