Abstract
This study investigates the role of transient receptor potential ankyrin 1 (TRPA1) in murine temporomandibular joint (TMJ) inflammatory hyperalgesia and the influence of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Two distinct murine models of TMJ pain and inflammation (zymosan and CFA) were established. Spontaneous pain-like behaviours were observed as unilateral front paw cheek wipes. Ipsilateral cheek blood flow was used as a measure of ongoing inflammation, which, to our knowledge, is a novel approach to assessing real-time inflammation in the TMJ. Joint tissue and trigeminal ganglia were collected for ex vivo investigation. Both zymosan and CFA induced a time-dependent increase in hyperalgesia and inflammation biomarkers. Zymosan induced a significant effect after 4 h, correlating with a significantly increased IL-1β protein expression. CFA (50 µg) induced a more sustained response. The TRPA1 receptor antagonist A967079 significantly inhibited hyper-nociception. The NLRP3 inhibitor MCC950 similarly inhibited hyper-nociception, also attenuating inflammatory markers. In the trigeminal ganglia, CFA-induced CGRP expression showed trends of inhibition by A967079, whilst lba1 immunofluorescence was significantly inhibited by A967079 and MCC950, where the effect of TRPA1 inhibition lasted up to 14 days. Our results show that stimulation of TRPA1 is key to the TMJ pain. However, the inflammasome inhibitor exhibited similar properties in attenuating these pain-like behaviours, in addition to some inflammatory markers. This indicates that in addition to the therapeutic targeting of TRPA1, NLRP3 inhibition may provide a novel therapeutic strategy for TMJ inflammation and pain.
Highlights
The temporomandibular joints (TMJ) encompass the joint area that connects the mandibular condyle to the temporal bone, consisting of an articular disc and the glenoid fossa
The CGRP expression appeared to be slightly increased in the Complete Freund’s Adjuvant (CFA)-treated group at day 5, with minimal changes observed in the mRNA at day 14 (Figure 6B,D). Both MCC950 and A967079 showed some trends to reduce CGRP expression at day 5, albeit not significantly, while minimal effects were observed at day 14 (Figure 6B,D). These results suggest that Iba1+ macrophages may play an important role in contributing to the CFA-induced hyperalgesia, and it can be partially targeted by both NLR family pyrin domain-containing 3 (NLRP3) and transient receptor potential ankyrin 1 (TRPA1) antagonists
We used two distinct unilateral models of TMJ inflammatory hyperalgesia, relevant to arthritis and obtained similar results to show: (i) ipsilateral painrelated behaviours as measured by monitoring front paw wiping, (ii) increased markers of TMJ inflammation as measured by a non-invasive technique to measure cheek skin blood flow as well as pro-IL1β/mature IL-1β expression, and (iii) for the first time, we show a dependence of the hyper-nociception and inflammatory phases on TRPA1 and NLRP3 in mouse Temporomandibular disorders (TMD) models
Summary
The temporomandibular joints (TMJ) encompass the joint area that connects the mandibular condyle (jaw) to the temporal bone (skull), consisting of an articular disc and the glenoid fossa. Pharmaceuticals 2021, 14, 1073 of conditions affecting the TMJ and surrounding areas, characterized by chronic joint and muscle pain, limited jaw movement, and clicking [1]. About 30% of TMD sufferers report the painful form of the disorders, of which 65% reported recurrent pain, mainly affecting both the joint and muscle areas [2,3]. The non-selective cation channel transient receptor potential ankyrin 1 (TRPA1) is localized to approximately 65–70% of C and Aδfiber nociceptive sensory neurons that express the TRP vanilloid 1 (TRPV1) [4]. These neurons release CGRP and are involved in the pain pathway [5,6]. We have previously shown a direct link between TRPA1 and the pain associated with joint inflammation [7,8]
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