Dataset Information

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

ABSTRACT:

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 PKC? translocation in vitro and on PKC? activation in vivo in dorsal root ganglia (DRG) neurons.

Experimental approach

Effects of CR4056 on bradykinin-induced PKC? translocation were studied in rat sensory neurons by immunocytochemistry. PKC? 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 PKC? translocation with very rapid and long-lasting activity. CR4056 decreased hyperalgesia and phospho-PKC? immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKC? translocation was blocked by pertussis toxin, implying that the intracellular pathways involved G_i proteins. The inhibition of PKC? translocation by CR4056 was independent of the ?₂ -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 PKC? translocation with other analgesics. Whether the inhibition of PKC? 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.

SUBMITTER: Vellani V

PROVIDER: S-EPMC6976787 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Vellani Vittorio V Sabatini Chiara C Milia Chiara C Caselli Gianfranco G Lanza Marco M Letari Ornella O Rovati Lucio Claudio LC Giacomoni Chiara C

British journal of pharmacology 20191107 1

<h4>Background and purpose</h4>CR4056 is a first-in-class imidazoline-2 (I<sub>2</sub> ) 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.<h4>Experimental approach</h4>Effects ...[more]

PMID: 31454418

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