## 1 Introduction
Pain is prevalent in initial phases due to the presence of synovitis and it may be associated with joint stiffness, limitation in mouth opening, increasing sensitivity to cold and damp [2]. However, the pathology of TMJOA is complex; the TMJ and its surrounding structures are involved in multifactorial processes [10]. Furthermore, the pathogenesis and underlying molecular mechanisms involved in TMJOA development remain unknown due to the limited self-healing ability of articular cartilage. TMJOA is one of the most difficult joint diseases, and currently there is no consensus treatment for complete remission. The therapeutic strategy of TMJOA mainly aims to prevent gradual destruction of cartilage and subchondoral bone, inducing bone remodeling, relieving joint pain, and restoring TMJ functions [10]. The decision for surgical management of TMJOA is based on the evaluation of the individual response to non-invasive management [3]. Surgical intervention, such as joint replacement with autologous bone or an artificial joint, does not fully restore the destroyed organ, and the long-term prognosis is uncertain, with some cases requiring a second operation; however, this treatment rarely restores the destroyed joint [1]. Common clinical treatments mainly include nonsurgical options, such as psychotherapy [11], physical therapy, occlusal stabilization splints, medication, and arthrocentesis, among which inter-articular injection of drugs is a crucial and common therapy aiming to relieve pain and improve jaw function [3; 10]. Sodium hyaluronate and glucocorticoid are the widely used drugs in the clinic, their strong anti-inflammatory effects are useful to relieve the pain of TMJOA patients for a long time. In recent years another promising potential therapy is the local injection of hyaluronic acid, which reduced histologic and bony morphometric measures of TMJ inflammation [12]. Currently, conventional pharmacologic interventions, such as non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics, are considered the primary management for painful TMJOA, reducing TMJ-related pain and inflammatory states [13]. Generally, applied pharmacologic therapy shows efficacy in pain relief but their long-term use is frequently associated with adverse effects, such as gastrointestinal and renal toxicity, related to prolonged use [10; 14]. A large number of supplementshave been tested for the treatment of TMD, but, for example, glucosamine and chondro have been studied with conflicting results, while others such as vitamin D and glucosamine in combination with hyaluronate, did not show any significant effect [2]. In this context, the growing need for new therapies to improve inflammatory pain have highlighted the role of natural products as a promising alternative for TMJOA, also encouraged by several scientific studies [15; 16; 17]. For example, it has been demonstrated that lectin from _Abelmochus esculentus_ was able to ameliorate the nociception in a rat model of formalin-induced TMJ inflammation [15]. The promising analgesic and anti-inflammatory role of lectin (0.001, 0.01, or 0.1 mg/kg) was mainly demonstrated through the reduction of tumor necrosis factor \(\alpha\) (TNF-\(\alpha\))-levels in the TMJ tissue, in the trigeminal ganglion, and subnucleus caudalis. It was also suggested that the central antinociceptive response was mediated by the activation of the \(\delta\) and \(\kappa\) receptors induced by _Abelmochus esculent_ lectin in this pre-clinical model of TMJ inflammation [15]. Another encouraging study concerned the role of the bioactive compound, namely sulfated polysaccharide, isolated from the marine organism red seaweed _Solieria filiformis_. The role in reducing the TMJ inflammatory hypernociception of these compounds was assessed in a rat model [16].