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

Abstract

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.

Osteoarthritis Pain in Old Mice Aggravates Neuroinflammation and Frailty: The Positive Effect of Morphine Treatment

“…A similar activation is present also in DRGs, where, as already reported by us and others [ 20 , 62 ] also ATF3 is upregulated. ATF3 is not detectable in intact primary sensory neurons but is upregulated in the nucleus of injured peripheral neurons, such as in rheumatoid arthritis and OA mouse models [ 24 , 63 , 64 ], suggesting the presence of primary afferent injury. The flow of activation from the nerve to DRGs then proceeds to the spinal cord, where we found relevant microgliosis demonstrated by the overexpression of microglia markers.…”

Macrophages and glial cells: Innate immune drivers of inflammatory arthritic pain perception from peripheral joints to the central nervous system

“…For instance, the superficial dorsal horn of mice with K/BxN serum transfer arthritis displayed increased staining of microglial IBA1 at early and late time points in the model ( 58 ). Microgliosis has also been described early in the model and at 5 and 10 weeks in an ankle joint with MIA-induced OA in rats ( 63 , 148 ). In both cases, intrathecal inhibition of microglia with minocycline inhibited mechanical allodynia ( 63 , 148 ).…”

“…Microgliosis has also been described early in the model and at 5 and 10 weeks in an ankle joint with MIA-induced OA in rats ( 63 , 148 ). In both cases, intrathecal inhibition of microglia with minocycline inhibited mechanical allodynia ( 63 , 148 ). In addition, in the murine CAIA model, hypersensitivity was correlated with the presence of reactive spinal microgliosis ( 18 ).…”

Therapeutic exercise interventions in rat models of arthritis

“…The dose of MIA and CFA varied significantly between research groups. Multiple groups have provided evidence that the dose of either compound impacts joint pathology, disease progression, and resulting pain behaviour outcomes ( Bourassa et al, 2020 , Gomes et al, 2013 ). Few studies that met inclusion criteria used models of inflammatory arthritis so it was not possible to draw comparisons between OA and inflammatory arthritis models.…”