Differential Involvement of t-SNARE Proteins and Signaling Pathways During PGE2-Induced TRPV1 Sensitization

Abstract

Prostaglandin E2 (PGE2) is a significant mediator of inflammatory pain that causes sensitization of the transient receptor potential vanilloid 1 (TRPV1) channels in primary sensory neurons. Previous research focused on intracellular signaling pathways; however, the role of vesicular trafficking mechanisms in TRPV1 sensitization is not fully elucidated. In this study, we examined whether PGE2-induced TRPV1 sensitization correlates with distinct regulation of t-SNARE proteins in dorsal root ganglia (DRG) and peripheral tissues, utilizing a rat model of inflammatory pain. We used behavioral tests, different inhibitors, DRG neuronal cultures, and protein expression tests. We observed that PGE2-induced sensitization correlates with a reduction in SNAP25 expression in DRG neurons and a decrease in syntaxin-1 expression in peripheral tissues. Pharmacological inhibition of various signaling pathways diminished PGE2-induced hyperalgesia in hyperalgesic priming model and modified t-SNARE protein expression. These results suggest, rather than definitively establish, the involvement of the following signaling pathways in capsaicin-induced mechanical allodynia: PKCε, cAMP, PLC, SNAP25, p38 MAPK, JNK MAPK, ERK-MAPK, PKC, PKA, CaMKII, CDK5, intracellular and extracellular Ca²⁺. The differential regulation of t-SNARE proteins may be linked to TRPV1 sensitization in a tissue-specific manner. Nonetheless, since only total protein levels were evaluated and no direct measurements of membrane trafficking were conducted, additional studies are necessary to elucidate the mechanistic role of t-SNARE proteins in TRPV1 surface localization and function.