Post-traumatic Hyperalgesia and Degeneration of Temporomandibular joints in mice: the role of nociceptive afferents

Abstract

Trauma to the temporomandibular joint (TMJ) can increase the incidence of developing temporomandibular disorder (TMD), and there is some controversy regarding the relationship between TMJ pain and degeneration. Considering the clinical implications of pain management, it is important to recognize whether it can affect the prognosis of TMJ degeneration. Recent studies have demonstrated that nociceptive afferents participate in bone remodeling via several pathways, suggesting that these afferents may be involved in both the perception of pain and the structural modulation of the TMJ. The specific impact of nociceptive afferents on TMJ pain and degeneration, however, remains ambiguous. We utilized the forced mouth opening (FMO) model on mice to address this issue. The FMO model resulted in increased mechanical hyperalgesia, as measured by the Von Frey (VF) test, spontaneous pain-like behaviors observed through the mouse grimace scale (MGS), and anxiety-like behaviors ascertained by the open-field test (OFT). These symptoms align with clinically relevant pain conditions such as spontaneous, mechanical, and function-evoked pain. Most TMJ afferents in the trigeminal ganglia (TG) were small peptidergic neurons expressing calcitonin gene-related peptides, whereas non-peptidergic TMJ afferents were comparatively scarce. Additionally, the FMO induced thinning of the condylar cartilage and degeneration of the subchondral bone, corroborating the model's ability to replicate post-traumatic hyperalgesia and TMJ condylar degeneration. Chemogenetic silencing of TRPV1-lineage afferents, using an inhibitory designer receptor exclusively activated by designer drugs (DREADD), lessened spontaneous pain-like behaviors but did not affect mechanical hyperalgesia in the skin overlying the TMJ. This silencing also modestly reduced FMO-induced subchondral bone degeneration without impacting cartilage degeneration. Our findings imply that TRPV1-lineage afferent fibers may not be the main factor in condylar degeneration following TMJ injury. Conclusively, our study results endorse the FMO model as a clinically relevant and translational approach for investigating post-traumatic, pain-like behaviors. Moreover, manipulating the TMJ nociceptive terminals may be effective in treating pain without aggravating degeneration after injury.