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. 2019 Sep;160(9):2036-2049.
doi: 10.1097/j.pain.0000000000001598.

Females have greater susceptibility to develop ongoing pain and central sensitization in a rat model of temporomandibular joint pain

Sébastien Sannajust  1   2 , Ian Imbert  1 , Victoria Eaton  1   2 , Terry Henderson  3 , Lucy Liaw  3 , Meghan May  1 , Mary F Barbe  4 , Tamara King  1   2
Affiliations

Females have greater susceptibility to develop ongoing pain and central sensitization in a rat model of temporomandibular joint pain

Sébastien Sannajust et al. Pain. 2019 Sep.

Abstract

Temporomandibular joint osteoarthritis (TMJOA) is a prevalent source of temporomandibular joint disorder (TMD). Women are more commonly diagnosed with TMD and are more likely to seek care at tertiary orofacial pain clinics. Limited knowledge regarding mechanisms underlying temporomandibular joint (TMJ) pain impairs development of improved pain management strategies. In a rat model of unilateral TMJOA, monosodium iodoacetate (MIA) produces joint pathology in a concentration-dependent manner. Unilateral MIA produces alterations in meal patterns in males and females without altering overnight time spent eating or weight across 2 weeks. Monosodium iodoacetate (80 mg/mL)-treated males develop ongoing pain within 2 weeks after MIA injection. Females develop ongoing pain at a 5-fold lower MIA concentration (16.6 mg/m). Monosodium iodoacetate (80 mg/mL)-treated males show spread of tactile hypersensitivity across the face during the first week after injection and then to the fore paws and hind paws during the second week after injection, indicating development of central sensitization. At the lower dose, female rats demonstrate a similar spread of tactile hypersensitivity, whereas male rats do not develop ongoing pain or spread of tactile hypersensitivity outside the area of the ipsilateral temporomandibular joint. These observations indicate that females have a higher susceptibility to development of ongoing pain and central sensitization compared with male rats that is not due to differences in MIA-induced joint pathology. This model of TMJOA pain can be used to explore sex differences in pain processes implicated in development of neuropathic pain, ongoing pain, and central sensitization, allowing for development of individualized strategies for prevention and treatment of TMD joint pain.

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Conflict of interest statement

Conflict of interest: The authors have no conflict of interest

Figures

Figure 1.
Figure 1.
A. Radiographic image of rat with needle inserted below root of the zygoma into the intra-articular space. B. Evans blue demonstrates the injection site located below the ear canal. Dissection of the injection site demonstrates Evans blue at the site of the TMJ condyle and mandible. C. H&E demonstrates pathology of the TMJ joint. The contralateral TMJ demonstrates normal structure of the temporal bone, articular disc (meniscus), synovium, and mandibular condyle. The inset demonstrates normal cellular organization in the surface of the condyle. F: fibrous layer; P: proliferative layer; H: hypertrophy layer; C: calcified layer; B: subchondral bone. Male rats treated with 80 mg/ml MIA demonstrate dramatic bone restructuring of both the temporal bone and mandibular condyle. Non-nucleated tissue replacement is apparent in the articular disc indicating formation of scar tissue. Synovitis is apparent and fibrinous exudates are observed in the synovial cavities. There is clear loss of regular alignment and multilayer arrangement of chondrocytes in the mandibular condyle. Female and male rats treated with 15 mg/ml MIA also demonstrate bone restructuring of both the mandibular fossa and condyle, although not to the degree observed in 80 mg/ml MIA treated rats. D) Pathology scores of MIA treated TMJ were significantly elevated, compared to the contralateral TMJ. Pathology scores of the ipsilateral TMJ from males treated with the 80 mg/ml MIA (high) were significantly higher than scores for ipsilateral TMJ from males (*p
Figure 2.
Figure 2.
H&E demonstrates low-dose MIA induced similar levels of pathology of the TMJ joint in female and male rats. The contralateral TMJ demonstrates normal structure of the temporal bone, articular disc (meniscus), synovium, and mandibular condyle which has normal cellular organization in the surface of the condyle. In MIA treated TMJ, there is clear loss of regular alignment and multilayer arrangement of chondrocytes in the mandibular condyle and the temporal bone. The articular surface of both the temporal bone and mandibular condyle demonstrate disorganized irregular surfaces. Female and male rats treated with low dose MIA also demonstrate enlargement of the articular disk and bone remodeling in the mandibular condyle. TB-temporal bone, AD-articular disk, MC-mandibular condyle, S-synovium. Call out images taken with 20x objective.
Figure 3.
Figure 3.
Toluidine blue stain confirms cartilage loss in the MIA treated TMJ condyle. Male rats treated with the high concentration of MIA demonstrate a loss of cartilage in the ipsilateral mandibular condyle. Low does MIA induced cartilage loss as indicated by diminished blue staining in the hypertrophic layer indicating cartilage loss with loss of chondrocytes on the TMJ condyle in both female and male TMJ. Call-out figures show cellular changes and disorganized irregular articular surfaces of the mandibular condyle and temporal bone in both female and male MIA treated TMJ. TB-temporal bone, AD-articular disk, MC-mandibular condyle, S-synovium. Images taken with 20x objective.
Figure 4:
Figure 4:
A) MicroCT images demonstrating bone remodeling of the mandibular condyle following 80 mg/ml MIA. B) Contralateral non-MIA treated bone are shown in the top row. Ipsilateral mandibular condyles received MIA. Bone remodeling of the ipsilateral mandibular condyle is apparent in female and male rats treated with 16.6 mg/ml MIA as well as in males treated with 80 mg/ml MIA when compared to the contralateral non-MIA treated bone. Left side of panel shows top down images of the mandibular condyle (transaxial views) illustrating trabecular bone thickening along with areas of bone loss in the condyle (yellow arrows). Similar levels of bone remodeling were observed in the female and male rats treated with 16.6 mg/ml MIA. Middle column of images shows lateral views of the condyles with areas of apparent bone erosion (yellow arrows) as well as formation of osteophytes and lipping (blue arrows) along the top edge. Right column of images of medial views of the mandibular condyle (right column) also demonstrate development of pitting along the condyle (dark blue arrows).
Figure 5:
Figure 5:
Meal pattern analysis of rats overnight 24 hrs, 7 days and 14 days post-MIA injection in male and female rats. A) Meal eating time for each meal (sec/meal) demonstrates decreased time spent eating in both saline and MIA treated male rats during the first observation period D1 post-injection. Males treated with 80 mg/ml MIA demonstrated reduced time spent eating through 7 days post-injection (***p####p<0.0001 vs saline). Time spent eating was equivalent between saline and MIA treated rats 14 days post-injection, with saline rats demonstrating increased time per meal compared to BL (**p<0.01 vs BL). B) Males treated with saline or 80 mg/ml MIA injections increased the total number of meals across the overnight period during the first observation period D1 post-injection. The number of meals returned to BL 7 days post-saline, but not post-MIA. Number of meals were equivalent in saline and MIA treated rats D14 post-MIA, ***p<0.001 vs BL; ####p<0.0001 vs saline). C. Females treated with 16.6 mg/ml MIA or saline demonstrated reduced time per meal during the first observation period (***p<0.001 vs BL). Saline treated females returned to pre-injection time per meal within 7 days of injection. MIA treated females showed persistent decreased time per meal7 and 14 days post injection compared to saline treated controls (#p<0.05; ##p<0.01 vs saline, ***p<0.001 vs BL). D. Females treated with 16.6 mg/ml MIA or saline demonstrated increased number of meals during the first observation period post-injection (****p<0.0001 vs BL). MIA treated females continued to show elevated number of meals compared to BL 7- and 14-days post-injection (***p<0.001 vs BL) but did not differ from the saline treated controls. E. Total time spent eating did not change in males treated with saline or MIA at any time-point. F. Females treated with saline demonstrated elevated time spent eating 7- and 14-days post-injection (#p<0.05 vs saline; *p<0.05 vs BL), MIA treated females did not show any changes in time spent eating. G. Weight gain over 14 days did not differ between saline and MIA treated male rats. H. Weight gain over 14 days did not differ between saline and MIA treated female rats. All graphs represent mean ± SEM, n=6 for all treatment groups.
Figure 6:
Figure 6:
A) Systemic duloxetine (30 mg/kg i.p.) attenuated MIA-induced tactile hypersensitivity within 15 min and fully reversed the hypersensitivity by 30 min in male rats treated with 80 mg/ml MIA, ****p
Figure 7:
Figure 7:
The time-course of MIA-induced tactile hypersensitivity was assessed at 5 sites to determine development of central sensitization: Diagram showing regions von Frey tested on rat (colors match the symbols on the graphs); A) Male rats treated with 80 mg/ml MIA developed tactile hypersensitivity at the ipsilateral TMJ test site within 1 day. Tactile hypersensitivity spread to periorbital test site within 3 days and the contralateral TMJ test site within 7 days post-injection; n=11–12. B) Males treated with 80 mg/ml MIA into the TMJ developed tactile hypersensitivity in the ipsilateral forepaw and hindpaw days 7 and 14 post-injection; n=9–12. Males treated with 80 mg/ml MIA into the TMJ developed tactile hypersensitivity in the ipsilateral forepaw and hindpaw days 7 and 14 post-injection; n=9–12. C. Female rats treated with 16.6 mg/ml MIA developed tactile hypersensitivity at the ipsilateral test site within 1 day. Tactile hypersensitivity spread to the periorbital test site within 3 days and to the contralateral TMJ test site within 14 days post-MIA; n=10–12. D) Females treated with 16.6 mg/ml MIA into the TMJ developed tactile hypersensitivity in the forepaw and hindpaw days 7 and 14 post-injection; n=9–10. E. Male rats treated with 16.6 mg/ml MIA developed hypersensitivity at the ipsilateral TMJ test site within 1 day but failed to show tactile hypersensitivity at the periorbital or contralateral TMJ test sites; n=12/group. F. Male rats treated with 16.6 mg/ml MIA failed to develop tactile hypersensitivity in the forepaw or hindpaw; n=9–12. For all graphs, ****p
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