143: Sex differences in spontaneous nociception in an osteoarthritis mouse model

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic secondary musculoskeletal pain, , , , , , , , , , Neuroimmunology, Behavioral studies

Background and Aims: Osteoarthritic pain is classically considered a nociceptive pain resulting from abnormal joint loading. Recently, the existence of a neuropathic component in osteoarthritic pain has been proposed in both human and rodent studies. Brain-derived neurotrophic factor (BDNF) in sensory neurons contributes to pain in male neuropathic pain models. In rodent models, the effects of neuropathic pain are greater in males than those in females across several behavioral paradigms. However, the sex differences in the monoiodoacetate-induced osteoarthritis model remain unclear. This study aimed to compare sex differences in pain-related behaviors and to examine BDNF expression in a monoiodoacetate-induced osteoarthritis model.

Methods: Male and female C57BL/6J mice, aged 8 weeks were used. The mice were randomly assigned to the osteoarthritis group or pain-free control group. The osteoarthritis model was induced by an intra-articular injection into the left knee joint of 10 μl monoiodoacetate in normal saline under anesthesia with isoflurane. The control mice received an intra-articular injection of normal saline. Pain-related behavioral responses were assessed by paw withdrawal threshold testing, and the open field test. BDNF mRNA expression in ipsilateral L3–L5 dorsal root ganglion was measured, at 5 days, 3 weeks, and 4 weeks after intra-articular injection, using quantitative real-time PCR.

Results: The paw withdrawal threshold was significantly decreased at 5 days after intra-articular injection in the osteoarthritis group in both sexes, compared to before the injection or pain-free control group (p<0.05). Time spent in the center, total distance traveled, and average velocity in the open field test were significantly decreased at 5 days after intra-articular injection in the osteoarthritis group, compared to pain-free controls in males (p<0.05), but not in females. BDNF mRNA expression in the dorsal root ganglion was significantly increased in the osteoarthritis model at 5 days in both sexes to a similar extent (p<0.05).

Conclusions: In various pain models, the sex-specific effects of BDNF are controversial and depend on the model tested as well as the site of BDNF release. BDNF may act as an autocrine or paracrine signal, activating pre-synaptic tropomyosin receptor kinase B receptors and regulating synaptic excitability in pain transmission. In the male osteoarthritis model, BDNF mRNA in the dorsal root ganglion was increased, and hyperalgesia was observed across behavioral tests. It is possible that BDNF in sensory neurons is transported to and released in the spinal dorsal horn, thereby contributing to the development of neuronal sensitization and pain hypersensitivity in osteoarthritis.

References: de la Rosa T, Llorca-Torralba M, Martínez-Cortés A, Romero-López-Alberca C, Berrocoso E. A Systematic Review and Meta-Analysis of Anxiety- and Depressive-Like Behaviors in Rodent Models of Neuropathic Pain. Biol Psychiatry Glob Open Sci. 2024; 4:100388.
Seibenhener ML, Wooten MC. Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp. 2015; 96:e52434.
Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB. Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci U S A. 1999; 96:7714–7718.

Presenting Author: Yui Fukushima
Submitting Author: Yui Fukushima

Senior Author: Kazuhiro Hayashi

IASP 2026 Global Year theme of Neuropathic Pain: No

• Mayuu Iwai: MS - Human Health Sciences, Faculty of Medicine, Kyoto University, Kyoto, Japan.
• Mei Yamada: BS - Human Health Sciences, Faculty of Medicine, Kyoto University, Kyoto, Japan.
• Joseph B. Lesnak: PhD - Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA.
• Ashley N. Plumb: PhD - Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA.
• Ryo Nakahara: PhD - Department of Rehabilitation Medicine, University of Washington, Seattle, WA, USA.
• Rina Okura: BS - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• Naoki Ooka: BS - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• Kenshiro Kashima: BS - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• Momoko Nagai-Tanima: PhD - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• Akira Ito: PhD - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• Shigehito Yamada: MD, PhD - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• Kazuhiro Hayashi: PhD - Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.