Inflammation induces Epac-protein kinase C alpha and epsilon signaling in TRPV1-mediated hyperalgesia.

Abstract

The exchange proteins activated by cAMP (Epacs) have been shown to play important roles in producing inflammation-induced nociception. Transient receptor potential vanilloid type 1 (TRPV1) is a major receptor processing thermal and chemosensitive nociceptive information. The role of Epacs in modulating the activity of TRPV1 has yet to be determined. Studying the effect of complete Freund adjuvant (CFA)-induced inflammation on capsaicin-activated TRPV1 nociceptive responses in dorsal root ganglia (DRG), we found that CFA produced a large increase in capsaicin-induced responses. The increase was inhibited by Epac1 and Epac2 antagonists. Thus, activation of Epacs is critical in producing enhancement in TRPV1-mediated responses under inflammatory conditions. In addition, the inflammation-induced enhancement of TRPV1 responses was blocked by PKCα and PKCε inhibitors, suggesting the essential roles of these PKCs in enhancing TRPV1 responses. To determine the mechanism underlying the Epac actions on TRPV1, we studied the effects of the Epac activator, 8-(4-chlorophenylthio)-2-O-methyl-cAMP (CPT), on capsaicin-induced nociceptive behavioral responses, capsaicin-activated currents, expression and membrane trafficking of PKC and TRPV1 in DRG. CPT was found to enhance capsaicin-induced nociception and ionic currents. The enhancement was inhibited by PKCα and PKCε inhibitors. In addition, CPT increased the expression of phosphorylated PKCα (pPKCα) and membrane TRPV1 expression in DRG. Studying the colocalization of TRPV1 and pPKCα or pPKCε in DRG slices prepared from CFA-treated rats, we found that pPKCα or pPKCε expressed with TRPV1 in different-sized neurons to exert differential influences on TRPV1 activity. Thus, Epac-PKC signaling is critically important in producing inflammation-induced potentiation of TRPV1 functions.

• Authors: Yanping Gu, Guangwen Li, Li-Yen Mae Huang
• Journal: Pain (Pain) Vol. 159 Issue 11 Pg. 2383-2393 (Nov 2018) ISSN: 1872-6623 [Electronic] United States
• PMID: 30015706 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Receptors, Purinergic P2X4
• TRPV Cation Channels
• Trpv1 protein, rat
• Erythromycin
• erythromycin propionate-N-acetylcysteinate
• Freund's Adjuvant
• Protein Kinase C-alpha
• Protein Kinase C-epsilon
• Capsaicin
• Acetylcysteine

Topics

• Acetylcysteine (analogs & derivatives, metabolism, pharmacology)
• Action Potentials (drug effects, physiology)
• Animals
• Biotinylation
• Capsaicin (toxicity)
• Cells, Cultured
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Erythromycin (analogs & derivatives, metabolism, pharmacology)
• Freund's Adjuvant (toxicity)
• Ganglia, Spinal (cytology)
• Hyperalgesia (pathology, physiopathology)
• Inflammation (chemically induced, enzymology)
• Male
• Neurons (drug effects, physiology)
• Patch-Clamp Techniques
• Protein Kinase C-alpha (metabolism)
• Protein Kinase C-epsilon (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P2X4 (metabolism)
• Signal Transduction (physiology)
• TRPV Cation Channels (metabolism)