According to the American Oropasial Pain Academy, temporomandibular disorders (TMDs) are defined as a group of disorders with masticatory muscles, temporomandibular joint (TMJ), and associated structures. TMDs are the second most common state of chronic muscle pain (Leboeuf-Yde et al., 2009). Pain is mostly seen in the masticatory muscles and anterior ears and may be exacerbated in chewing or other jaw activities. Other findings include joint sounds, asymmetric jaw movement, masticatory muscle hypertrophy, muscle fatigue, headache, bruxism, palpation sensitivity, and limited jaw movement due to the difficult opening of the mouth (Tjakkes et al., 2010). Pain, functional, and psycho-social disorders associated with TMD affect the quality of life more negatively than other oral conditions (Dahlstrm & Carlsson, 2010). However, the mechanisms in the pathophysiology of chronic pain caused by TMDs are not fully understood and this makes it difficult to implement accurate diagnosis and appropriate treatment protocols (Arendt-Nielsen et al., 2015). The existing evidence shows that approximately 50%of the risk of the development of chronic pain is affected by genetic and epigenetic changes in pain-reduced systems and sensitizing processes of peripheral and central nervous systems (Diatchenko et al., 2013).

It has been reported that heredity for nociceptive and analgesic sensitivities in mice is estimated to be between 28% and 75% and as one of the candidate pain genes, the single-nucleotide polymorphisms (SNPs) in Catecholamine-O-Metiltransferase (COMT) gene (Mogil, 1999). There are two types of this enzyme: soluble-COMT (S-COMT) containing 221 amino acids and membrane-bound -COMT (MB-COMT) containing 271 amino acids. Both enzymes are coded by the COMT gene in the 22nd chromosome. The specific location is in the long arm in 22q11.21 (Gen ID 1312). The COMT consists of 27222 nucleotides and contains six exons, five introns, and two promoter zones (P1 and P2) (Nissinen & Männistö, 2010). COMT neutralizes a wide variety of catechol substrates, including catecholamines and catechol estrogens, and acts as a key modulator of dopaminergic and adrenergic/noradrenergic neurotransmission, including ascending and descending pain pathways (Tenhunen et al., 1994). At an early date like 1965, Marbach and Levitt showed the increased levels of urine catecholamine metabolites in patients with jaw joints and facial pain, and that it refers to decreased erythrocytic COMT activity, revealing that it could play a role in chronic pain (Marbach & Levitt, 1976). Low COMT activity in central regions produces a high dopaminergic tone with contrasting antinociceptive effects. It has been shown that polymorphisms in the COMT gene are often associated with the sensitivity processes and hyperalgesia and allodynia of the central nervous system in previous studies, and are significantly associated with increased TMD development risk (Mladenovic et al., 2016, Younger et al., 2010).

Catecholamines are connected to two different receptors called α and β adrenergic receptors (ADR).

β2-adrenergic receptors (ADB2) are connected to a G protein and are also expressed in the regions of the central and peripheral nervous system in pain transmission (Hartung et al., 2014). Human ADB2 is an intron-free gen on the 5q31–32.81 chromosome. Stimulation of this receptor leads to nociceptors that produce allodynia through activation of intracellular kinases. Also, the stimulation of these facilitates the transmission of pain through the release of proinflammatory molecules. It has been shown in a previous study that catecholamines increase their excitability by stimulating ADRB2 receptors when they are present in primary afferent nociceptor nerve endings (Khasar et al., 2003). Due to the existence of different haplotypes encoding β-adrenergic receptors, more than a 10-fold risk of developing TMD has been found between individuals with higher and lower ADRB2 expression. These results show that both positive and negative imbalances in the ADRB2 gene function increase vulnerability to chronic pain conditions such as TMD through different pathophysiological ways (Diatchenko et al., 2006). Therefore, it is seen that changes in the presence of polymorphisms in the COMT and ADRB2 genes may be associated with permanent TMD conditions. There are few reports in the literature investigating the relationship between COMT and ADRB2 gene polymorphisms and TMD, and different results have been presented (Bonato et al., 2021, Brancher et al., 2019a, de Souza Tesch et al., 2020, Michelotti et al., 2014). Although a recent meta-analysis study supports a significant relationship between genetic polymorphisms in the COMT gene and TMD, the authors stated that the results should be interpreted with caution due to the paucity of studies and population heterogeneity (Brancher et al., 2021). As far as we know, there is no study investigating the relationship between gene polymorphisms in COMT, ADRB2, and TMD in the Turkish population. This study aimed to evaluate the possible relationship between polymorphisms in COMT (rs9332377) and ADRB2 (rs2053044) genes with TMDs. The h1 hypothesis to be tested is that COMT and ADRB2 gene polymorphisms are associated with TMD.