CR4056, a powerful analgesic imidazoline-2 receptor ligand, inhibits the inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons
| Autor: | Chiara Sabatini, Lucio C. Rovati, Chiara Giacomoni, Gianfranco Caselli, Ornella Letari, Marco Lanza, Vittorio Vellani, Chiara Milia |
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| Přispěvatelé: | Vellani, V, Sabatini, C, Milia, C, Caselli, G, Lanza, M, Letari, O, Rovati, L, Giacomoni, C |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Male Sensory Receptor Cells medicine.drug_class Freund's Adjuvant Imidazoline receptor Pain Chromosomal translocation Protein Kinase C-epsilon Pharmacology Pertussis toxin 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Amino Acid Sequence Phosphorylation Rats Wistar Receptor Cells Cultured Inflammation Analgesics Dose-Response Relationship Drug Chemistry Cell Membrane Imidazoles CR4056 PKCε Ligand (biochemistry) Research Papers Rats 030104 developmental biology Hyperalgesia Quinazolines Imidazoline Receptors medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Br J Pharmacol |
| ISSN: | 1476-5381 |
| Popis: | BACKGROUND AND PURPOSE: CR4056 is a first‐in‐class imidazoline‐2 (I(2)) 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 G(i) proteins. The inhibition of PKCε translocation by CR4056 was independent of the α(2)‐adrenoeceptor and, surprisingly, was also independent of idazoxan‐sensitive I(2) binding sites. The I(2) 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 I(2) receptors should be further investigated. If so, this would be a new mode of action of a highly specific I(2) receptor ligand. |
| Databáze: | OpenAIRE |
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