Resolvin receptor signaling in trigeminal sensory neurons

Project Summary/Abstract
Pain management in craniofacial pathology is a major clinical challenge. Although many people suffer from
chronic inflammatory pain caused by a temporomandibular joint disorder (TMJD) and other chronic oral and
facial diseases, there is no effective treatment. Our previous study demonstrated that lipid mediators derived
from omega-3 polyunsaturated fatty acids such as resolvin E1 (RvE1) were effective in inhibiting inflammatory
pain by regulating TRPV1. However, it is unclear whether RvE1 can inhibit TMJ pain in the trigeminal nervous
system, the role of its receptor ChemR23, and its relevance to clinical translation.
We found from preliminary data that ChemR23 is co-expressed with TRPV1 using the ATAC-Seq database,
RvE1 was decreased in the TMJ-CFA model using ELISA detection, and RvE1 can reduce TMJ pain using the
biting force method. Based on this, we suggest that a RvE1/ChemR23 signaling pathway resolves TMJ pain by
suppressing TRPV1 function.
In Aim1, we predict that the RvE1/ChemR23 pathway will be downregulated during the TMJ-CFA model. To
address our hypothesis, we will examine measuring of change of RvE1 level in TMJ-tissue, TGs, saliva, and
serum in TMJ-CFA mice to confirm whether RvE1 can affect pain using the ELISA method. And we will test the
ChemR23 expression level change and TRPV1 binding activity in TGs using western blot after the generation of
the TMJ-CFA model. We will measure how much ChemR23 is expressed in TMJ-innervated TG in the TMJ-CFA
model using flow cytometry.
In Aim2, we will investigate the mechanism of pain suppression through ChemR23/TRPV1 through animal
behavioral experiments. To know the RvE1 can block the TRPV1-induced pain in TG, we will cause acute
trigeminal pain by injecting TRPV1 agonist capsaicin into the whisker pad. In addition, we will use unilateral CFA
injection to the TMJ to test the hypothesis that RvE1 inhibits TMJ pain via ChemR23. To that end, we'll use local
whisker pads or TMJ injections of the AAV1 virus to reduce ChemR23 expression in TG neurons.
In Aim3, we will examine whether ChemR23 and TRPV1 mechanisms can be applied to human sensory neurons
through Co-IP assay and real-time PCR using Human DRG and TG provided by Co-I. We will compare the
differences in expression levels and Co-IP activity of DRGs and TGs.
We propose a novel molecular mechanism for the resolution of tertiary pain where RvE1-induced ChemR23
activation can inhibit TRPV1 signaling. If completed, including future directions, this proposal will provide a new
path for TMJ pain control. It will enable the development of new drugs aimed at TMJ and broaden our
understanding of the disease. And this proposal can provide fundamental data for future research, such as
investigating the role of additional resolvins and other TRP channels in human serum and chronic animal models.

Grant Number: 5R03DE032394-02
NIH Institute/Center: NIH
Principal Investigator: Sangsu Bang