Apoptosis in displaced temporomandibular joint disc with and without reduction: an immunohistochemical study

J Oral Pathol Med (2011) 40 : 103–110 Internal derangement (ID) of the temporomandibular joint (TMJ) is due to an abnormal relationship of the articular disc to the mandibular condyle, glenoid fossa and articular eminence. The two most common types of internal derangement are anterior disc displacement with (ADDwR) and without reduction (ADDwoR). Disc displacement is associated with degenerative tissue changes. The histological features of discs from patients with TMJ ID reflect a general remodelling caused by abnormal loading. A correlation has been demonstrated between TMJ ID and apoptosis. Few investigations have addressed the role of apoptosis or caspase activity in TMJ ID. The apoptosis activation process was studied in different areas of discs from 18 patients with ID (both ADDwR and ADDwoR) and four cadavers (controls), with emphasis on the expression of caspase 3, whose activation makes the death process irreversible. The results showed a greater proportion of caspase 3‐positive cells in ADDwR and ADDwoR than in control discs. Immunopositivity also varied between disc areas; in particular, in ADDwoR sections labelled cells were significantly more numerous (P < 0.01) in the posterior disc attachment than in the anterior and intermediate bands. In addition, a significantly greater proportion of labelled cells was seen in the anterior (+) and intermediate (++) band of ADDwR compared with ADDwoR discs both bands (P < 0.05). These data suggest the importance of programmed cell death in the progression of TMJ ID.     

Analysis of 70Kd heat shock protein expression in patients with internal derangement of the temporomandibular joint

Recent studies have demonstrated that the expression of heat shock protein (HSP) was enhanced under stress in joint diseases, such as rheumatoid arthritis and osteoarthritis. The purpose of this study was to analyze the expression of 70Kd HSP in patients with internal derangement of the temporomandibular joint (TMJ) by immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods. For immunohistochemistry, 5 extirpated discs and 16 synovial biopsy specimens from patients with TMJ internal derangement and 2 extirpated discs from normal subjects were examined. For ELISA, synovial fluid from 11 patients with TMJ internal derangement and from 6 normal volunteers were investigated. The results showed that the 70Kd HSP staining intensity in chondrocytes around the damaged area of the articular discs from patients with TMJ internal derangement was higher than that in chondrocytes in control specimens. In addition, 70Kd HSP expression in synovial fluid from patients with TMJ internal derangement was slightly higher than that in normal subjects. These findings suggest that elevated 70Kd HSP expression is related to the progression of TMJ internal derangement.     

Dysplasia-dependent abnormalities of the temporomandibular joint

The purpose of this study was to reveal the relationship between temporomandibular joint (TMJ) dysfunction and dysplasia of connective tissue (DCT). This investigation included 53 (34 female and 19 male) patients with TMJ internal derangement (ID) and 53 controls; 24 patients with marked and 53 patients with mild dysfunction of this joint. The symptoms of DCT (such as scoliosis, general joint hypermorbility) and TMJ ID were revealed. Results of this study prove that DCT is one of etiological factors of TMJ ID. The relationship between type of ID and severity of DCT was revealed.     

Angiogenesis in the human temporomandibular joint studied by immunohistochemistry for CD34 antigen

The CD34 antigen is a sensitive marker of vascular endothelium and angiogenesis. Thus, we examined the expression of CD34 in 20 human temporomandibular joint (TMJ) samples with internal derangement and in 10 control specimens by an immunohistological technique using paraffin-embedded tissue and specific anti-human CD34 monoclonal antibody. In the control specimens, CD34 was observed sporadically within the TMJ discs. On the other hand, in the internal derangement specimens, CD34 was found frequently in the walls of blood capillaries within the TMJ discs. In the synovial membrane, CD34 was detected frequently in the walls of many blood capillaries in both the controls and the internal derangement specimens. Indeed, CD34 expression in internal derangement specimens was more intense than in control specimens. In the posterior loose connective tissue of the bilaminar zone, and in the anterior loose connective tissue between the upper and lower lamellae of the anterior capsular wall, CD34 was detected in abundance in the walls of blood capillaries both of the controls and the internal derangement specimens. Generally, CD34 was found rarely in the walls of large blood vessels. The presence of CD34 is suggested to be correlated with the process of angiogenesis induced by internal derangement of the TMJ.     

Specific expression of substance P in synovial tissues of patients with symptomatic, non-reducing internal derangement of the temporomandibular joint: comparison with clinical findings

Our aim was to find out the extent of expression of substance P in synovial tissue from the human temporomandibular joints (TMJ) with symptomatic, non-reducing internal derangement, and to investigate the relationship between substance P and clinical findings. Fifty-four joints in 54 patients were examined immunohistochemically. Specimens of synovial tissue from 10 joints in 8 subjects with habitual dislocation of the TMJ with no pain were examined as controls. Cells that stained for substance P were found mainly among the endothelial cells in the blood vessels beneath the lining cells in synovial tissues from 47 of the 54 joints (87%) with internal derangement and from 5 of the 10 control joints. The extent score of cells that stained for substance P in joints with internal derangement was significantly higher than that in controls (p=0.02). The extent score of these cells did not correlate with pain in the joint or the degree of synovitis. These results suggest that substance P may have some roles in both the physiological and pathological conditions in patients with symptomatic internal derangement of the TMJ.     

Expression of chemerin in the synovial fluid of patients with temporomandibular joint disorders

The synovial membrane and fluid are significantly involved in the pathogenesis of temporomandibular joint (TMJ) disorders. This study aimed to investigate the relation between levels of chemerin in the synovial fluid (SF) of patients with TMJ disorder and their relationship. Sixty samples of SF were obtained from patients with an internal derangement (ID) or osteoarthritis (OA). Chemerin in the SF was examined by enzyme‐linked immunosorbent assay (ELISA). The results showed greater levels of chemerin in the SF of patients with OA than ID. While chemerin levels were positively correlated with pain scores, they were inversely correlated with MMO. Chemerin levels increased progressively as the disorder stage became more severe. The findings of this study suggest that chemerin in SF may play role as a predisposing factor and may represent a novel potential prognostic biochemical marker in the pathogenesis of TMJ disorders.     

Risk factors for temporomandibular joint pain in patients with disc displacement without reduction - a magnetic resonance imaging study

The purpose of this study was to evaluate whether the magnetic resonance (MR) imaging variables of temporomandibular joint (TMJ) internal derangement, osteoarthrosis and/or effusion may predict the presence of pain in patients with a clinical disorder of an internal derangement type (ID)-III. The relationship between TMJ ID-III pain and TMJ internal derangement, osteoarthrosis and effusion was analysed in MR images of 84 TMJs in 42 patients with a clinical unilateral diagnosis of TMJ ID-III pain. Criteria for including a TMJ ID-III pain patient were report of orofacial pain referred to the TMJ, with the presence of unilateral TMJ pain during palpation, function and/or unassisted or assisted mandibular opening. Bilateral sagittal and coronal MR images were obtained to establish the presence or absence of TMJ internal derangement, osteoarthrosis and effusion. Using chi-square analysis for pair-wise comparison, the data showed a significant relationship between the MR imaging findings of TMJ ID-III pain and those of internal derangement (P=0.01) and effusion (P=0.00). Of the MR imaging variables considered simultaneously in the multiple logistic regression analysis, osteoarthrosis (P=0.82) and effusion (P=0.08) dropped out as non-significant in the diagnostic TMJ pain group when compared with the TMJ non-pain group. The odds ratio that a TMJ with an internal derangement type of disk displacement without reduction might belong to the pain group was strong (2.7:1) and highly significant (P=0.00). Significant increases in risk of TMJ pain occurred with 'disk displacement without reduction in combination with osteoarthrosis' (5.2:1) (P=0.00) and/or 'disk displacement without reduction in combination with osteoarthrosis and effusion' (6.6:1) (P=0.00). The results suggest that TMJ pain is related to internal derangement, osteoarthrosis and effusion. However, the data re-emphasize the aspect that these MR imaging variables may not be regarded as the unique and dominant factors in defining TMJ pain instances.     

Diagnosing TMJ internal derangement and osteoarthritis with magnetic resonance imaging.

BACKGROUND: The authors conducted a study to investigate the relationship between the presence of temporomandibular joint, or TMJ, pain and magnetic resonance imaging, or MRI, findings of internal derangement, or ID, and arthritis, or OA. METHODS: The authors studied 131 consecutively seen TMJ pain patients. Their criteria for including a patient in the study were report of unilateral orofacial pain referred to TMJ and the presence of unilateral TMJ pain during palpation, function, and unassisted or assisted mandibular opening. The authors took bilateral sagittal and coronal MRIs to establish the presence or absence of TMJ ID, OA or both. RESULTS: When the authors compared TMJ side-related data from all subjects, they found a significant relationship between the clinical findings of TMJ pain and the MRI diagnoses of TMJ ID (P = .000) and TMJ OA (P = .013). They also found a significant relationship between the MRI diagnosis of TMJ ID type and that of TMJ OA (P = .000). The authors used the kappa statistical test and found poor diagnostic agreement between the presence of TMJ pain and the MRI diagnosis of TMJ ID (kappa = 0.21), TMJ OA (kappa = 0.15), and TMJ ID and OA combined (kappa = 0.18). CONCLUSIONS: The study's findings suggest that while clinical pain is related to TMJ-related MRI findings, the presence of clinical pain is not a reliable predictor of TMJ ID, OA or both. CLINICAL IMPLICATIONS: Using MRI to supplement clinical findings of TMJ pain appears warranted and necessary to establish the presence or absence of TMJ ID.     

Magnetic resonance imaging findings of internal derangement and effusion in patients with unilateral temporomandibular joint pain.

OBJECTIVES: The purpose of this study was to investigate the relationship between the presence of temporomandibular joint (TMJ) pain and the magnetic resonance (MR) imaging findings of internal derangement (ID) and effusion. STUDY DESIGN: The study was comprised of 41 consecutive patients with TMJ pain. Criteria for including a patient were report of unilateral pain near the TMJ, with the presence of unilateral TMJ pain during palpation, function, and/or unassisted or assisted mandibular opening, and the absence of a specific clinical TMJ-related diagnosis of disk displacement with or without reduction. Bilateral sagittal and coronal MR images were obtained to establish the presence or absence of TMJ ID or effusion, or both. RESULTS: Comparison of the TMJ side-related data showed a significant relationship between the clinical finding of TMJ pain and the MR imaging diagnoses of TMJ ID (P =.001), and TMJ effusion (P =.004). Furthermore, there was a significant relationship between the MR imaging diagnosis of TMJ ID and TMJ effusion (P =.000). Use of the kappa statistic test indicated poor diagnostic agreement between the presence of TMJ pain and the MR imaging diagnosis of TMJ ID (kappa = 0.34), TMJ effusion (kappa = 0.32), and TMJ ID and effusion (kappa = 0.27). CONCLUSIONS: The study's findings suggest that although clinical pain is correlated with TMJ-related MR imaging findings, clinical pain in and of itself is not reliable for predicting the presence of TMJ ID or effusion, or both. Therefore, MR imaging appears to be a warranted and necessary supplement to the clinical findings.     

The expression of substance P in human temporomandibular joint samples: an immunohistochemical study

The expression of neuropeptide substance P was examined in 18 human temporomandibular joint (TMJ) samples with internal derangement of the TMJ, and in 10 control specimens. The examination was carried out using an immunohistological technique, using paraffin-embedded tissue and specific anti-human substance P polyclonal antibody. We noted five characteristic distribution patterns of substance P expression: at the nerves' fibre bundles in the connective tissues of the anterior and/or posterior attachment; around the blood vessels in the attachments; at the margin of the TMJ disc and synovial membrane layer; on the surface of hypertrophic synovial membranes with inflammation and proliferation; and around the newly formed capillaries in the TMJ discs. In TMJs with internal derangement associated with severe pain, we found distinct substance P expression in most of the specimens. The expression was particularly intense at the margin of the TMJ disc and synovial membrane layer, on the surface of hypertrophic synovial membranes and around the newly formed capillaries in the TMJ discs. The clinical symptoms of internal derangement of the TMJ are thought to be associated with the degree of synovitis. We conclude that the expression of substance P seems to be closely related to histopathological changes of the human TMJ with internal derangement.     

The expression of vascular endothelial growth factor in synovial tissues in patients with internal derangement of the temporomandibular joint

OBJECTIVE: The aim of this study was to elucidate the expression and localization of vascular endothelial growth factor (VEGF) in synovial tissue taken from the temporomandibular joint (TMJ) with internal derangement (ID) and discuss the role of VEGF in the pathogenesis of ID. STUDY DESIGN: Through the use of an immunohistochemical technique, 39 TMJs in 37 patients were examined. As controls, synovial tissue specimens from 6 joints in 6 patients with habitual dislocation were also examined. RESULTS: In the synovial tissue from 35 of the patients with ID, expression of VEGF was observed in the synovial lining cells, in the endothelial cells of the blood vessels, and in the fibroblasts. In contrast, expression of VEGF was found in the TMJ tissue from only 2 of the controls. The percentage of VEGF-positive cells in the ID specimens was significantly higher than that in the habitual dislocation specimens (P < .02), and the expression of VEGF significantly correlated with the arthroscopic synovitis score (P = .004). CONCLUSION: These results suggest that the expression of VEGF is upregulated and involved in the development of inflammatory changes in synovial tissues in TMJs with ID.     

Magnetic resonance imaging evaluation of temporomandibular joint disc deformities in relation to type of disc displacement.

PURPOSE: This study was undertaken to assess the relationship between the temporomandibular joint (TMJ) disc deformity and the type of internal derangement. PATIENTS AND METHODS: One hundred thirty-three TMJs of 72 patients (53 female and 19 male) with intracapsular dysfunction were studied using clinical and magnetic resonance imaging examinations. RESULTS: Of the 133 TMJ discs, 41.35% had no deformity, whereas 18% of the discs were folded, 19.55% were lengthened, 9.77% were round, 7.51% were biconvex, and 3.75% had thick posterior bands. The frequency of disc deformity was greater with anterior disc displacement without reduction than in cases of anterior disc displacement with reduction (P <.001). Folded and round discs were most common in cases with TMJ anterior disc displacement without reduction (P <.0001). An increase in length was seen in 56.75% of the cases with anterior disc displacement with reduction, whereas 100% of nonreducing discs were mainly folded or rounded. Crepitation was correlated with folded and round disc deformities, whereas lengthening was the feature of reducing discs associated with early and intermediate clicking. CONCLUSIONS: The results show that the degenerative changes in the TMJ disc are influenced by the degree and the type of disc displacement. The more advanced the internal derangement, the more deteriorated the disc configuration.     

Apoptosis in temporomandibular joint disc with internal derangement involves mitochondrial-dependent pathways. An in vivo study

Abstract

Objective. Two main apoptosis pathways have been identified: an extrinsic (or death receptor-mediated) and an intrinsic (or mitochondrial) pathway. Apoptotic cell death through the extrinsic pathway has just been described in temporomandibular joint disc (TMJ) with internal derangement (ID); in contrast, no data are available on the involvement of the intrinsic pathway in this tissue. The aim of this work was to investigate whether the intrinsic pathway participates in apoptosis activation in patients with TMJ ID and anterior disc displacement without reduction. Materials and methods. Apoptosis activation was studied in TMJ discs from 15 patients with ID and in six unaffected discs using bcl-2–associated X protein (bax), B-cell lymphoma 2 (bcl-2), cytochrome c and caspase 9 immunohistochemistry. A correlation was sought between immunohistochemical findings and degree of disc damage. Results. None of the pathological TMJ disc sections were immunopositive for bcl-2; negative bcl-2 immunostaining was detected in affected discs; cytochrome c and caspase 9 immunoreactivity was greater in pathological compared to unaffected discs; the difference was significant and correlated with histopathological degeneration score data (Spearman's rho = 0.617). Conclusion. The present findings suggest that in-human TMJ with ID and anterior disc displacement without reduction of cell apoptosis occurs, at least partly, via the mitochondrial pathway, which contributes to the subsequent disc degeneration. These data may have clinical implications and could help devise improved treatment strategies.     

Temporomandibular joint pain: relationship to internal derangement type, osteoarthrosis, and synovial fluid mediator level of tumor necrosis factor-alpha

OBJECTIVES: The purpose of this study was to investigate whether patients with temporomandibular joint (TMJ)-related pain classified as capsulitis/synovitis may be linked to magnetic resonance imaging (MRI) findings of internal derangement, osteoarthrosis, or the synovial fluid aspirate findings of tumor necrosis factor-alpha (TNF-alpha) level. STUDY DESIGN: The study comprised 23 patients with temporomandibular disorders (TMD), who had nonchronic pain (pain onset < or =6 months) and a unilateral TMJ-related diagnosis of capsulitis/synovitis. Bilateral sagittal and coronal magnetic resonance images were obtained to establish the presence or absence of internal derangement, osteoarthrosis, or both. TMJ synovial fluid aspirates were obtained from the pain and contralateral nonpain sides to determine the TNF-alpha level. RESULTS: Comparison of the TMJ side-related data showed a significant relationship between the clinical TMD diagnosis of capsulitis/synovitis and the MRI diagnoses of TMJ internal derangement (P =.002) and of TMJ internal derangement type (P =.04). The mean TNF-alpha level in synovial fluid aspirates from TMJs assigned a clinical TMD diagnosis of capsulitis/synovitis was significantly higher than in those obtained from contralateral nonpain sides (P =.001). There was no correlation between the clinical diagnosis of capsulitis/synovitis and the MRI diagnosis of TMJ osteoarthrosis (P =.13) or between the MRI diagnosis of TMJ osteoarthrosis and that of TMJ internal derangement (P =.70) or TMJ internal derangement type (P =.33). CONCLUSIONS: The results suggest that the TMJ pain condition of capsulitis/synovitis is related to TMJ-side specific MRI diagnoses of internal derangement and internal derangement type, and synovial fluid aspirate findings of TNF-alpha level. The data confirm the concept of elevated mediator level as a diagnostic approach for patients presenting with TMJ-related pain. MRI and synovial fluid aspirates may be used as diagnostic methods for evaluating TMJ-related pain conditions.     

Bradykinin expression in synovial tissues and synovial fluids obtained from patients with internal derangement of the temporomandibular joint

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of the potent pro-inflammatory properties. The purpose of this study is to investigate the expression of bradykinin in patients with internal derangement of the temporomandibular joint (TMJ). We examined 33 TMJ synovial biopsy specimens from 31 patients with internal derangement of the TMJ by an immunohistochemical technique using specific antibodies. We also determined the concentration of bradykinin in 20 synovial fluids from 18 patients with TMJ internal derangement by enzyme-linked immunosorbent assay. These data were compared with those of the control subjects. Bradykinin was predominantly localized in the synovial lining cell layer of TMJ samples obtained from patients with TMJ internal derangement. Bradykinin was also detected in 19 patients' TMJ synovial fluids and the average of bradykinin concentration in the synovial fluids of patients was higher than that of the healthy controls. Although a statistically significant correlation was not observed, these findings support the hypothesis that bradykinin may also be involved in the pathogenesis of TMJ pain and synovitis.     

关节液蛋白含量与颞下颌关节疼痛患者影像学特征的对照研究

目的　探讨关节液中的蛋白浓度与关节影像学特征性表现及疼痛的关系。方法　采用磁共振成像 (MRI)金标准对4 0例单侧颞下颌关节 (TMJ)疼痛患者进行结构紊乱、骨关节炎及关节渗液的诊断 ,并在关节上腔冲洗治疗时收集关节液标本 ,以不存在结构紊乱、骨关节炎及关节渗液的关节液标本为对照 ,15侧无症状志愿者的关节液为正常对照 ;采用双金鸡宁酸法检测关节液中蛋白浓度。结果　患者关节液中蛋白含量的高低与结构紊乱、关节渗液及骨关节炎均无相关性 ;患者关节液中蛋白含量与正常人蛋白含量无差异。结论　关节液中的蛋白水平不能反映在影像学上代表关节炎症的结构紊乱、骨关节炎及渗出液关节的炎症状态及疼痛。     

Relationship between temporomandibular joint pain and magnetic resonance imaging findings of internal derangement

In terms of clinical decision-making in instances of temporomandibular disorders (TMD) and orofacial pain, there is controversy in the literature over the diagnostic significance of the temporomandibular joint (TMJ)-related variable disk-condyle relationship (DCR). The purpose of this study was to investigate whether in patients with TMJ-related pain, the variable of TMJ pain may be linked to magnetic resonance (MR) imaging findings of internal derangement (ID). The study comprised 163 consecutive TMJ pain patients. Criteria for including a patient were report of orofacial pain referred to the TMJ, and the presence of uni- or bilateral TMJ pain during palpation, during function, and/or during unassisted or assisted mandibular opening. Bilateral sagittal and coronal MR images were obtained to establish the prevalence of TMJ ID types. Analysis of the data revealed the presence of TMJ pain to be associated with significantly more MR imaging diagnoses of ID than an absence of ID (P<0.001), and disk displacement without reduction than disk displacement with reduction (P<0.001). Using chi-square analysis, the results showed a significant relationship between the presence of TMJ-related pain and the MR imaging diagnosis of TMJ ID (P=0.001), and TMJ ID type (P=0.000). Use of the Kappa statistical test indicated poor diagnostic agreement between the presence of TMJ pain and the MR imaging diagnosis of ID (K=0.16). The results suggest that the clinical variable of TMJ pain may have a significant effect on the prevalences of MR imaging diagnoses of TMJ ID. The data confirm the biological concept of DCR as a diagnostic approach in patients with signs and symptoms of TMJ-related pain.     

Bradykinin Expression in Synovial Tissues and Synovial Fluids Obtained from Patients with Internal Derangement of the Temporomandibular Joint

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of the potent pro-inflammatory properties. The purpose of this study is to investigate the expression of bradykinin in patients with internal derangement of the temporomandibular joint (TMJ). We examined 33 TMJ synovial biopsy specimens from 31 patients with internal derangement of the TMJ by an immunohistochemical technique using specific antibodies. We also determined the concentration of bradykinin in 20 synovial fluids from 18 patients with TMJ internal derangement by enzyme-linked immunosorbent assay. These data were compared with those of the control subjects. Bradykinin was predominantly localized in the synovial lining cell layer of TMJ samples obtained from patients with TMJ internal derangement. Bradykinin was also detected in 19 patients' TMJ synovial fluids and the average of bradykinin concentration in the synovial fluids of patients was higher than that of the healthy controls. Although a statistically significant correlation was not observed, these findings support the hypothesis that bradykinin may also be involved in the pathogenesis of TMJ pain and synovitis.     

MRI评价颞下颌关节镜盘复位固定术的短期疗效

目的:用MRI评价颞下颌关节(temporomandibular joint,TMJ)镜关节盘复位固定术的短期疗效。方法:2004- 08—2007-03期间,共对639例(764侧关节)Ⅱ～Ⅴ期TMJ结构紊乱(internal derangement,ID)患者进行了关节镜治疗,所有患者手术前及术后1～7 d进行MRI检查。根据我们制定的成功标准,在髁突矢状位上选用内、中、外3个不同的层面进行手术前后关节盘的位置比较,从而评价手术疗效。标准制定如下:若3个层面完全复位,则疗效定为"优";2个层面完全复位,则疗效定为"良";仅1个层面或完全未复位则疗效定为"差"。将"优"和"良"定为有效(注:若术前仅有1个或2个1/3层面移位者,要求均被复位才算有效)。结果:764侧关节中,术后MRI显示729侧关节为"优",占95.42%;24侧关节为"良",占3.14%;11侧关节为"差",约1.44%,对评价为"差"的关节进行了二次关节镜手术或开放性手术。结论:经手术前后MRI对比验证,颞下颌关节镜关节盘复位固定术能有效地将关节盘复位,但其稳定性尚需进一步评价。     

Relationship of calcitonin gene-related peptide in synovial tissues and temporomandibular joint pain in humans

OBJECTIVE: To elucidate the expression of calcitonin gene-related peptide (CGRP) in synovial tissue taken from the human temporomandibular joint (TMJ) with internal derangement, and discuss the relationship between CGRP and joint pain. STUDY DESIGN: Using an immunohistochemical technique, 48 joints in 48 patients were examined. As controls, synovial tissue specimens from 7 joints with habitual dislocation without pain were also examined. RESULTS: In all of the internal derangement and control subjects, CGRP-positive cells were observed in the connective tissues around the blood vessels beneath the lining cells. The extent score of CGRP was significantly higher in the internal derangement group than in the control group (P=.033). There was a significant positive correlation between the extent score of CGRP and joint pain (P=.036, r=0.30). CONCLUSIONS: These results suggest that the expression of CGRP is increased in the synovial tissues from patients with internal derangement, and that CGRP seems to play an important role in the mechanism of pain production in patients with symptomatic internal derangement.