Identification and validation of LPA/LPAR signaling as a target for the treatment of temporomandibular disorder pain

ABSTRACT
Current pharmacologic therapies for TMD pain are largely ineffective and plagued with side effects because their
mechanisms of action to TMD pain have not been validated. Validation of potential pain targets for TMD pain
can facilitate the development of mechanism-based approaches. Emerging evidence suggests that
lysophosphatidic acid (LPA)/LPA receptor (LPAR) signaling is a promising target for spinally-mediated
neuropathic pain. However, whether it contributes to trigeminally-mediated TMD pain, which involves
anatomically and functionally unique target tissues and distinct etiology, is not known. In addition, there are
several roadblocks which hamper the translatability of LPA/LPAR to pain therapeutics: 1) this potential pain
target has been rarely validated in human tissues; 2) its mechanisms in pain, particularly where and how it drives
pain, remain poorly understood; and 3) its addiction liability has not been evaluated. The objective of this project
is to identify and validate LPA/LPAR in trigeminal ganglion (TG) sensory neurons as a novel mechanistic target
for the treatment of TMD pain. Our preliminary results revealed that LPA levels in the plasma and TGs are
elevated in mouse models of chronic TMD. In line with results from mice, we also found that LPA in plasma is
increased in TMD patients and, importantly, positively correlated with pain intensity ratings. In addition,
immunostaining analysis showed that LPAR are localized in both mouse and human TG sensory neurons.
Systemic inhibition of LPA/LPAR or local inhibition of LPA/LPAR in TG neurons-innervating TMJ tissues
attenuated mechanical pain and masticatory pain in mouse models of TMD, while they did not show addictive
effects. Moreover, electrophysiological recording revealed LPA/LPAR can sensitize PIEZO2, a mechanical
transducer, in response to mechanical stimuli. Therefore, we hypothesize that LPA/LPAR in TG neurons drive
TMD pain via PIEZO2 ion channel. This central hypothesis will be tested in experiments that seek to: 1)
determine the contribution of elevated LPA to TMD pain; 2) dissect the contribution of LPAR in TG sensory
neurons to LPA-driven TMD pain; and 3) examine whether LPA/LPAR in TG neurons drive TMD pain via PIEZO2
ion channel. The proposed experiments will include rigorous validation using complementary clinically-relevant
animal models, pain measures, human tissues and replication of key experiments across laboratories. We will
also perform extensive experiments evaluating the addiction liability of LPA/LPAR. Success completion of this
project will substantively advance our understanding of TMD pain mechanisms. Importantly, the proposal is
clinically significant because it validates LPA/LPAR as a mechanistic target with exciting potential to prevent
chronic TMD pain.

Grant Number: 1R01DE032676-01A1
NIH Institute/Center: NIH
Principal Investigator: Yong Chen