Pain-related behavior is associated with increased joint innervation, ipsilateral dorsal horn gliosis, and dorsal root ganglia activating transcription factor 3 expression in a rat ankle joint model of osteoarthritis

INTRODUCTION: Osteoarthritis (OA)-associated pain is often poorly managed, as our understanding of the underlying pain mechanisms remains limited. The known variability from patient to patient in pain control could be a consequence of a neuropathic component in OA. METHODS: We used a rat monoiodoacetate model of the ankle joint to study the time-course of the development of pain-related behavior and pathological changes in the joint, dorsal root ganglia (DRG), and spinal cord, and to investigate drug treatments effects. RESULTS: Mechanical hypersensitivity and loss of mobility (as assessed by treadmill) were detected from 4 weeks after monoiodoacetate. Cold allodynia was detected from 5 weeks. Using histology and x-ray microtomography, we confirmed significant cartilage and bone degeneration at 5 and 10 weeks. We detected increased nociceptive peptidergic and sympathetic fiber innervation in the subchondral bone and synovium at 5 and 10 weeks. Sympathetic blockade at 5 weeks reduced pain-related behavior. At 5 weeks, we observed, ipsilaterally only, DRG neurons expressing anti-activating transcription factor 3, a neuronal stress marker. In the spinal cord, there was microgliosis at 5 and 10 weeks, and astrocytosis at 10 weeks only. Inhibition of glia at 5 weeks with minocycline and fluorocitrate alleviated mechanical allodynia. CONCLUSION: Besides a detailed time-course of pathology in this OA model, we show evidence of contributions of the sympathetic nervous system and dorsal horn glia to pain mechanisms. In addition, late activating transcription factor 3 expression in the DRG that coincides with these changes provides evidence in support of a neuropathic component in OA pain.