139: Intra-articular cannabidiol reduces hypersensitivity in MIA-induced TMJ osteoarthritis model

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic secondary musculoskeletal pain, , , , , , , , , , Pharmacological interventions, Assessment and Measurement of Pain/Nociception, Behavioral studies

Background and Aims: Osteoarthritis (OA) of the temporomandibular joint (TMJ) is a highly prevalent condition associated with chronic pain, functional impairment, and a substantial reduction in quality of life. The endocannabinoid system has emerged as a promising therapeutic target for OA, and cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has demonstrated anti-inflammatory, analgesic, and neuroprotective effects in experimental models. This study aimed to investigate whether intra-articular administration of CBD into the TMJ attenuates orofacial mechanical hypersensitivity in rats with monoiodoacetate (MIA)-induced TMJ OA.

Methods: Male Wistar Hannover rats were allocated into seven groups (n = 4/group): SHAM + vehicle (MCT), SHAM + CBD (100 µg), SHAM + CBD (300 µg), MIA (2 mg) + CBD (100 µg), MIA (2 mg) + CBD (300 µg), MIA (4 mg) + CBD (100 µg), and MIA (4 mg) + CBD (300 µg). TMJ OA was induced by bilateral intra-articular injection of MIA on day 0. After induction, CBD treatment was initiated in the experimental OA groups via intra-articular injections (50 µL) for four consecutive weeks. Orofacial mechanical sensitivity was assessed using the von Frey test at baseline and at 4 and 8 weeks after MIA injection.

Results: At the end of the experimental period, animals exposed to the higher MIA dose and treated with CBD exhibited a significant increase in the orofacial mechanical threshold, indicating a reduction in mechanical hypersensitivity, particularly under conditions of more severe joint degeneration. No significant changes in mechanical sensitivity were observed in SHAM animals treated with CBD.

Conclusions: These findings demonstrate that intra-articular CBD administration effectively reduces orofacial mechanical hypersensitivity in rats with MIA-induced TMJ OA, especially in advanced degenerative conditions, supporting the potential of CBD as a local therapeutic strategy for pain management associated with TMJ degeneration.

References: Abbadi, W., Z. Kara Beit, and N. M. Al-Khanati. 2022. “Arthrocentesis, Injectable Platelet-Rich Plasma and Combination of Both Protocols of Temporomandibular Joint Disorders Management: A Single-Blinded Randomized Clinical Trial.” Cureus 14 (11): e31396.

Abbass, M. M. S., D. Rady, S. El Moshy, I. Ahmed Radwan, A. S. Wadan, C. E. Dörfer, and K. M. F. El-Sayed. 2024. “The Temporomandibular Joint and the Human Body: A New Perspective on Cross Talk.” Dentistry Journal 12 (11): 357.

Al-Moraissi, E. A., K. Al-Otaibi, A. A. Almaweri, R. M. Bastos, O. L. Haas Junior, and A. G. Amran. 2024. “Treatment of Painful Temporomandibular Joint Disc Displacement without Reduction: Network Meta-Analysis of Randomized Clinical Trials.” International Journal of Oral and Maxillofacial Surgery 53 (7): 584–595.

Asadpour, N., Z. Shooshtari, M. Kazemian, M. Gholami, N. Vatanparast, and S. Samieirad. 2022. “Combined Platelet-Rich Plasma and Hyaluronic Acid Can Reduce Pain in Patients Undergoing Arthrocentesis for Temporomandibular Joint Osteoarthritis.” Journal of Oral and Maxillofacial Surgery 80 (9): 1474–1485.

Bawa, Z., D. Lewis, P. D. Gavin, R. Libinaki, L. Joubran, M. El-Tamimy, G. Taylor, R. Meltzer, M. Bedoya-Pérez, R. C. Kevin, and I. S. McGregor. 2024. “An Open-Label Feasibility Trial of Transdermal Cannabidiol for Hand Osteoarthritis.” Scientific Reports 14 (1): 11792.

Brucki, S. M. D., et al. 2015. “Cannabinoids in Neurology – Brazilian Academy of Neurology.” Arquivos de Neuro-Psiquiatria 73 (4): 334–342.

Chang, H.-A., Y.-P. Liu, C.-S. Tung, C.-C. Chang, N.-S. Tzeng, and S.-Y. Huang. 2014. “Effects of REM Sleep Deprivation on Sensorimotor Gating and Startle Habituation in Rats: Role of Social Isolation in Early Development.” Neuroscience Letters 575: 63–67.

Chen, D. 2022. “Osteoarthritis: A Complicated Joint Disease Requiring Extensive Studies with Multiple Approaches.” Journal of Orthopaedic Translation 32: 130.

Chen, Y., X. Zhang, C. Xia, L. Tang, M. E. Chen, S. Huang, J. He, and Z. Li. 2025. “Characteristics of Temporomandibular Joint Osteoarthritis Patients with Condylar Erosion: A Retrospective Cross-Sectional Study.” Journal of Oral Rehabilitation 52 (2): 208–221. =

Chung, M. K., S. Wang, I. Alshanqiti, J. Hu, and J. Y. Ro. 2023. “The Degeneration-Pain Relationship in the Temporomandibular Joint: Current Understandings and Rodent Models.” Frontiers in Pain Research 4: 1038808.

Cömert Kiliç, S., and M. Güngörmüş. 2016. “Is Arthrocentesis plus Platelet-Rich Plasma Superior to Arthrocentesis plus Hyaluronic Acid for the Treatment of Temporomandibular Joint Osteoarthritis: A Randomized Clinical Trial.” International Journal of Oral and Maxillofacial Surgery 45 (12): 1538–1544.

Dinges, Z. M., R. K. Phillips, C. M. Lively, and F. Bashey. 2022. “Post-Association Barrier to Host Switching Maintained Despite Strong Selection in a Novel Mutualism.” Ecology and Evolution 12 (6): e9011

Dunn, S. L., J. M. Wilkinson, A. Crawford, R. A. D. Bunning, and C. L. Le Maitre. 2016. “Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies.” Cannabis and Cannabinoid Research 1 (1): 3–15.

Frane, N., E. Stapleton, C. Iturriaga, M. Ganz, V. Rasquinha, and R. Duarte. 2022. “Cannabidiol as a Treatment for Arthritis and Joint Pain: An Exploratory Cross-Sectional Study.” Journal of Cannabis Research 4 (1): 47.

Fuentes, R., C. Veuthey, A. Arias, D. Saravia, and N. E. Ottone. 2017. “Injection in Temporomandibular Joint of Rats: Description of Technical Protocol.” Polish Journal of Veterinary Sciences 20 (2): 207–211. https://doi.org/10.1515/pjvs-2017-0025.

Gao, L., M. Cucchiarini, and H. Madry. 2020. “Cyst Formation in the Subchondral Bone Following Cartilage Repair.” Clinical and Translational Medicine 10 (8): e248.

Gondim, D. V., J. C. Araújo, A. L. Cavalcante, A. Havt, J. da S. Quetz, G. A. Brito, R. de A. Ribeiro, and M. Lima Vale. 2012. “CB1 and CB2 Contribute to Antinociceptive and Anti-Inflammatory Effects of Electroacupuncture on Experimental Arthritis of the Rat Temporomandibular Joint.” Canadian Journal of Physiology and Pharmacology 90 (11): 1479–1489.

Görürgöz, C., M. İçen, M. H. Kurt, S. Aksoy, B. Bakırarar, I. Rozylo-Kalinowska, and K. Orhan. 2023. “Degenerative Changes of the Mandibular Condyle in Relation to the Temporomandibular Joint Space, Gender and Age: A Multicenter CBCT Study.” Dental and Medical Problems 60 (1): 127–135.

Greenbaum, T., N. Ravhon, D. Barshai, A. Emodi-Perlman, and L. Kalichman. 2025. “Proprioceptive Test for the Temporomandibular Joint: An Intra- and Inter-Rater Reliability Study with Healthy Adults.” Dental and Medical Problems 62 (3): 487–492.

Guarda-Nardini, L., M. Meneghini, S. Zegdene, and D. Manfredini. 2021. “Temporomandibular Joint Arthrocentesis in Patients with Degenerative Joint Disease: A 10- to 22-Year Follow-up.” Journal of Oral & Facial Pain and Headache 35 (2): 113–118.

Guingamp, C., P. Gegout-Pottie, L. Philippe, B. Terlain, P. Netter, and P. Gillet. 1997. “Mono-Iodoacetate-Induced Experimental Osteoarthritis: A Dose-Response Study of Loss of Mobility, Morphology, and Biochemistry.” Arthritis & Rheumatism 40 (9): 1670–1679.

Hammell, D. C., L.-P. Zhang, F. Ma, S. M. Abshire, S. L. McIlwrath, A. L. Stinchcomb, and K. N. Westlund. 2016. “Transdermal Cannabidiol Reduces Inflammation and Pain-Related Behaviours in a Rat Model of Arthritis.” European Journal of Pain 20 (6): 936–948.

Hegab, A. F., H. I. A. A. Hameed, A. M. Hassaneen, and A. Hyder. 2023. “Synergistic Effect of Platelet Rich Plasma with Hyaluronic Acid Injection Following Arthrocentesis to Reduce Pain and Improve Function in TMJ Osteoarthritis.” Journal of Stomatology, Oral and Maxillofacial Surgery 124 (1S): 101340.

Işık, G., S. Kenç, B. Özveri Koyuncu, S. Günbay, and T. Günbay. 2022. “Injectable Platelet-Rich Fibrin as Treatment for Temporomandibular Joint Osteoarthritis: A Randomized Controlled Clinical Trial.” Journal of Cranio-Maxillofacial Surgery 50 (7): 576–582.

Khajuria, D. K., V. Karuppagounder, I. Nowak, D. E. Sepulveda, G. S. Lewis, C. C. Norbury, W. M. Raup-Konsavage, K. E. Vrana, F. Kamal, and R. A. Elbarbary. 2023. “Cannabidiol and Cannabigerol, Nonpsychotropic Cannabinoids, as Analgesics That Effectively Manage Bone Fracture Pain and Promote Healing in Mice.” Journal of Bone and Mineral Research 38 (11): 1560–1576.

Klasser, G. D., and R. de Leeuw. 2018. Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management. 6th ed. Chicago: Quintessence Publishing.

Kogan, N. M., E. Melamed, E. Wasserman, B. Raphael, A. Breuer, K. S. Stok, R. Sondergaard, A. V. Escudero, S. Baraghithy, M. Attar-Namdar, S. Friedlander-Barenboim, N. Mathavan, H. Isaksson, R. Mechoulam, R. Müller, A. Bajayo, Y. Gabet, and I. Bab. 2015. “Cannabidiol, a Major Non-Psychotropic Cannabis Constituent, Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.” Journal of Bone and Mineral Research 30 (10): 1905–1913.

Kwon, M., D. Nam, and J. Kim. 2023. “Pathological Characteristics of Monosodium Iodoacetate-Induced Osteoarthritis in Rats.” Tissue Engineering and Regenerative Medicine 20 (3): 435–446. https://doi.org/10.1007/s13770-023-00520-5.

Lane, N. E., K. Brandt, G. Hawker, E. Peeva, E. Schreyer, W. Tsuji, and M. C. Hochberg. 2011. “OARSI–FDA Initiative: Defining the Disease State of Osteoarthritis.” Osteoarthritis and Cartilage 19 (5): 478–482.

Lawrence, R. C., D. T. Felson, C. G. Helmick, L. M. Arnold, H. Choi, R. A. Deyo, S. Gabriel, R. Hirsch, M. C. Hochberg, and G. G. Hunder. 2008. “Estimates of the Prevalence of Arthritis and Other Rheumatic Conditions in the United States. Part II.” Arthritis & Rheumatism 58 (1): 26–35.

Leite-Panissi, C. R. A., B. B. de Paula, J. K. Neubert, and R. M. Caudle. 2023. “Influence of TRPV1 on Thermal Nociception in Rats with Temporomandibular Joint Persistent Inflammation Evaluated by the Operant Orofacial Pain Assessment Device (OPAD).” Journal of Pain Research 16: 2047–2062.

Li, J., K. Ma, D. Yi, C. D. Oh, and D. Chen. 2020. “Nociceptive Behavioural Assessments in Mouse Models of Temporomandibular Joint Disorders.” International Journal of Oral Science 12 (1): 26.

Man, G. S., and G. Mologhianu. 2014. “Osteoarthritis Pathogenesis: A Complex Process That Involves the Entire Joint.” Journal of Medicine and Life 7 (1): 37–41.

Marker, C. L., and J. D. Pomonis. 2012. “The Monosodium Iodoacetate Model of Osteoarthritis Pain in the Rat.” In Methods in Molecular Biology, vol. 851, 239–248.

Morais, S. V., N. G. Czeczko, O. Malafaia, J. M. Ribas Filho, J. B. Garcia, M. T. Miguel, C. Zini, and A. G. Massignan. 2016. “Osteoarthritis Model Induced by Intra-Articular Monosodium Iodoacetate in Rats Knee.” Acta Cirúrgica Brasileira 31 (11): 765–773.

Napimoga, M. H., B. B. Benatti, F. O. Lima, P. M. Alves, A. C. Campos, D. R. Pena-Dos-Santos, F. P. Severino, F. Q. Cunha, and F. S. Guimarães. 2009. “Cannabidiol Decreases Bone Resorption by Inhibiting RANK/RANKL Expression and Pro-Inflammatory Cytokines during Experimental Periodontitis in Rats.” International Immunopharmacology 9 (2): 216–222.

Nascimento, G. C., B. B. de Paula, R. F. Gerlach, and C. R. A. Leite-Panissi. 2021. “Temporomandibular Inflammation Regulates the Matrix Metalloproteinases MMP-2 and MMP-9 in Limbic Structures.” Journal of Cellular Physiology 236 (9): 6571–6580.

Ning, W., G. Schmalz, P. Li, and S. Huang. 2022. “Oral Health-Related Quality of Life in Patients with Osteoarthritis of the Temporomandibular Joint: Results of a Systematic Review.” Journal of Oral Rehabilitation 49 (11): 1106–1114.

Nitecka-Buchta, A., A. Nowak-Wachol, K. Wachol, K. Walczyńska-Dragon, P. Olczyk, O. Batoryna, W. Kempa, and S. Baron. 2019. “Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD: A Randomized, Double-Blind Trial.” Journal of Clinical Medicine 8 (11): 1886.

O’Brien, M., and J. J. McDougall. 2018. “Cannabis and Joints: Scientific Evidence for the Alleviation of Osteoarthritis Pain by Cannabinoids.” Current Opinion in Pharmacology 40: 104–109.

de Oliveira, A. C., A. P. Macedo, and A. C. Shimano. 2024. “Effects of Cannabidiol on Bone Quality in Ovariectomized Rats.” Calcified Tissue International 115 (5): 700–711.

Ostrowska, M., W. Maśliński, M. Prochorec-Sobieszek, M. Nieciecki, and I. Sudoł-Szopińska. 2018. “Cartilage and Bone Damage in Rheumatoid Arthritis.” Reumatologia 56 (2): 111–120.

Patikorn, C., O. Nerapusee, K. Soontornvipart, K. Lawonyawut, K. Musikpodok, K. Waleethanaphan, and P. Anantachoti. 2023. “Efficacy and Safety of Cannabidiol for the Treatment of Canine Osteoarthritis: A Systematic Review and Meta-Analysis of Animal Intervention Studies.” Frontiers in Veterinary Science 10: 1248417.

Poulsen, L., C. Børsting, C. Tomas, F. González-Andrade, R. Lopez-Pulles, J. González-Solórzano, and N. Morling. 2011. “Typing of Amerindian Kichwas and Mestizos from Ecuador with the SNPforID Multiplex.” Forensic Science International: Genetics 5 (4): e105–e107.

Philpott, H. T., M. O’Brien, and J. J. McDougall. 2017. “Attenuation of Early Phase Inflammation by Cannabidiol Prevents Pain and Nerve Damage in Rat Osteoarthritis.” Pain 158 (12): 2442–2451.

Schiffman, E., R. Ohrbach, E. Truelove, J. Look, G. Anderson, J.-P. Goulet, T. List, P. Svensson, Y. Gonzalez, and F. Lobbezoo. 2014. “Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications.” Journal of Oral & Facial Pain and Headache 28 (1): 6–27.

Silva, M. A. G., L. L. Q. Pantoja, K. L. Dutra-Horstmann, J. Valladares-Neto, F. L. Wolff, A. L. Porporatti, E. N. S. Guerra, and G. De Luca Canto. 2020. “Prevalence of Degenerative Disease in Temporomandibular Disorder Patients with Disc Displacement.” Journal of Cranio-Maxillofacial Surgery 48 (10): 942–955.

Spadon-Brito, L. G., C. S. P. Souza, A. M. Mélo, M. A. D. P. Calças, M. O. Melchior, F. L. Vieira, F. C. Lopes-Olhê, J. F. Santiago Junior, L. V. Magri, and J. F. Mazzi-Chaves. 2025. “Effectiveness of Treatments for Temporomandibular Joint Osteoarthritis: A Systematic Review and Meta-Analysis.” Clinical Oral Investigations 29 (11): 513.

Raoof, M., E. Ashrafganjoui, R. Kooshki, M. Abbasnejad, J. Haghani, S. Amanpour, and M. R. Zarei. 2018. “Effect of Chronic Stress on Capsaicin-Induced Dental Nociception in a Model of Pulpitis in Rats.” Archives of Oral Biology 85: 154–159.

Schuelert, N., C. Zhang, A. J. Mogg, L. M. Broad, D. L. Hepburn, E. S. Nisenbaum, M. P. Johnson, and J. J. McDougall. 2010. “Paradoxical Effects of the Cannabinoid CB2 Receptor Agonist GW405833 on Rat Osteoarthritic Knee Joint Pain.” Osteoarthritis and Cartilage 18: 1536–1543.

Sillmann, Y. M., J. L. G. C. Monteiro, M. Haugstad, B. Burris, D. A. Keith, S. Handa, and F. P. S. Guastaldi. 2025. “Intra-Articular Injection of Orthobiologics for Temporomandibular Joint Osteoarthritis: A Systematic Review of Randomized Controlled Trials.” International Journal of Oral and Maxillofacial Surgery 54 (7): 624–638.

Takahashi, I., T. Matsuzaki, and M. Hoso. 2017. “Long-Term Histopathological Developments in Knee-Joint Components in a Rat Model of Osteoarthritis Induced by Monosodium Iodoacetate.” Journal of Physical Therapy Science 29 (4): 590–597.

Tepecik, T., and E. Gedik. 2025. “Efficacy of Adjunctive Injectable Platelet-Rich Fibrin as a First-Line Treatment in Temporomandibular Joint Osteoarthritis: A Retrospective Cohort Study.” International Journal of Oral and Maxillofacial Surgery 54 (7): 639–646

Tesch, R. S., T. B. B. Calcia, and D. De Nordenflycht. 2024. “Unveiling MRI-Based Structural Phenotypes in Temporomandibular Joint Osteoarthritis: Implications for Clinical Practice and Research.” Dental Press Journal of Orthodontics 29 (4): e24spe4.

Tong, L., H. Yu, X. Huang, J. Shen, G. Xiao, L. Chen, H. Wang, L. Xing, and D. Chen. 2022. “Current Understanding of Osteoarthritis Pathogenesis and Relevant New Approaches.” Bone Research 10 (1): 60.

Vela, J., L. Dreyer, K. K. Petersen, L. Arendt-Nielsen, K. S. Duch, and S. Kristensen. 2022. “Cannabidiol Treatment in Hand Osteoarthritis and Psoriatic Arthritis: A Randomized, Double-Blind, Placebo-Controlled Trial.” Pain 163 (6): 1206–1214.

Vicenzi, C. B., D. J. Stein, J. M. de Castro, B. L. Silveira, A. D. S. Melo, E. M. Meyer Callai, F. Visioli, W. Caumo, A. S. de Quevedo, J. K. Neubert, and I. L. S. Torres. 2025. “Decreased Anxiety-like Behavior and Trigeminal Ganglion BDNF Levels Persist in Rats with Temporomandibular Joint Arthritis Even after Resolution of the Nociceptive Process.” Neuroscience Letters 851: 138166.

Waites, K. B., D. M. Crabb, A. E. Ratliff, W. M. Geisler, T. P. Atkinson, and L. Xiao. 2023. “Latest Advances in Laboratory Detection of Mycoplasma genitalium.” Journal of Clinical Microbiology 61 (3): e0079021.

Wang, G. Y. F., X. Q. Shi, W. Wu, M. Gueorguieva, M. Yang, and J. Zhang. 2018. “Sustained and Repeated Mouth Opening Leads to Development of Painful Temporomandibular Disorders Involving Macrophage/Microglia Activation in Mice.” Pain 159 (7): 1277–1288.

Wang, X.-D., X.-X. Kou, D.-Q. He, M.-M. Zeng, Z. Meng, R.-Y. Bi, Y. Liu, J.-N. Zhang, Y.-H. Gan, and Y.-H. Zhou. 2012. “Progression of Cartilage Degradation, Bone Resorption and Pain in Rat Temporomandibular Joint Osteoarthritis Induced by Injection of Iodoacetate.” PLOS ONE 7 (9): e45036.

Yun, S. Y., Y. Kim, H. Kim, and B. K. Lee. 2023. “Effective Technical Protocol for Producing a Mono-Iodoacetate-Induced Temporomandibular Joint Osteoarthritis in a Rat Model.” Tissue Engineering Part C: Methods 29 (9): 438–445.

Zhang, Y., N. Lu, Y. Xue, M. Zhang, Y. Li, Y. Si, X. Bian, Y. Jia, and Y. Wang. 2012. “Expression of Immunoglobulin-Like Transcript (ILT)2 and ILT3 in Human Gastric Cancer and Its Clinical Significance.” Molecular Medicine Reports 5 (4): 910–916. https://doi.org/10.3892/mmr.2012.744.

Presenting Author: Luiz Guilherme Spadon-Brito
Submitting Author: Luiz Guilherme Spadon de Brito

Senior Author: Luiz Guilherme Spadon-Brito

IASP 2026 Global Year theme of Neuropathic Pain: No

• Gabrielle Jacob - University of São Paulo
• Caio Sberni Pinheiro de Souza - University of São Paulo
• Fabiane Carneiro Lopes-Olhê - University of São Paulo
• Elaine Aparecida Del Bem - University of São Paulo
• Glauce Crivelaro do Nascimento - University of São Paulo
• Laís Valencise Magri - University of São Paulo
• Jardel Francisco Mazzi-Chaves - University of São Paulo