CR4056, a powerful analgesic imidazoline-2 receptor ligand, inhibits the inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons.

Autor:	Vellani, Vittorio, Sabatini, Chiara, Milia, Chiara, Caselli, Gianfranco, Lanza, Marco, Letari, Ornella, Rovati, Lucio Claudio, Giacomoni, Chiara
Předmět:	DORSAL root ganglia PERTUSSIS toxin BINDING sites KNEE pain LABORATORY animals ANALGESIC effectiveness DRUG receptors RESEARCH CELL culture PAIN HETEROCYCLIC compounds SENSORY receptors CELL membranes ANALGESICS ANIMAL experimentation INFLAMMATION RESEARCH methodology MEDICAL cooperation EVALUATION research IMIDAZOLES RATS COMPARATIVE studies TRANSFERASES DOSE-effect relationship in pharmacology RESEARCH funding SOLUTION (Chemistry) AMINO acids PHOSPHORYLATION PHARMACODYNAMICS
Zdroj:	British Journal of Pharmacology; Jan2020, Vol. 177 Issue 1, p48-64, 17p, 7 Graphs
Abstrakt:	Background and Purpose: CR4056 is a first-in-class imidazoline-2 (I2 ) receptor ligand characterized by potent analgesic activity in different experimental animal models of pain. In a recent phase II clinical trial, CR4056 effectively reduced pain in patients with knee osteoarthritis. In the present study, we investigated the effects of CR4056 on PKCε translocation in vitro and on PKCε activation in vivo in dorsal root ganglia (DRG) neurons.Experimental Approach: Effects of CR4056 on bradykinin-induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant-treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals.Key Results: CR4056 inhibited PKCε translocation with very rapid and long-lasting activity. CR4056 decreased hyperalgesia and phospho-PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved Gi proteins. The inhibition of PKCε translocation by CR4056 was independent of the α2 -adrenoeceptor and, surprisingly, was also independent of idazoxan-sensitive I2 binding sites. The I2 agonist 2BFI had no effect alone but potentiated the activity of low concentrations of CR4056.Conclusions and Implications: Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I2 receptors should be further investigated. If so, this would be a new mode of action of a highly specific I2 receptor ligand. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.