Changes in GABAA Receptor Function Is Dependent on Osteoarthritis Pain State

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      Osteoarthritis pain is a heterogeneous pain state. Mid-stage osteoarthritis is associated with pain during joint use that abates during rest and can be managed with non-steroidal anti-inflammatory agents (NSAIDs). Advanced osteoarthritis is characterized by development of persistent ongoing pain that is resistant to NSAIDs. Mechanistic differences underlying these different osteoarthritis pain states are poorly understood. This study investigated the hypothesis that changes in spinal GABAA receptor signaling is dependent on the characteristics of the chronic pain state. A murine model of monosodium iodoacetate (MIA)-induced knee joint osteoarthritis (OA) in males and females was used. Mice with mid-stage OA demonstrate weight asymmetry without a persistent ongoing pain state. Mice with advanced OA develop both weight asymmetry and persistent ongoing pain. Control mice received intra-articular saline. Alterations in GABAA receptors were investigated using spinal administration of the GABAA agonist (muscimol) and antagonist (bicuculline). In mice with mid-stage OA, spinal muscimol normalized weight asymmetry whereas spinal bicuculline did not alter weight asymmetry. Conversely, in mice with advanced OA, spinal muscimol failed to alter weight asymmetry whereas bicuculline normalized weight bearing. Further, in mice with advanced OA, muscimol induced conditioned place aversion, indicated worsening of joint pain, whereas bicuculline induced conditioned place preference, indicating pain relief. Restoring KCC2 function through spinal administration of CLP290 reversed weight asymmetry in mice with advanced but not mid-stage OA. These data indicate that GABAA receptors induce net inhibition in mid-stage OA, a chronic pain state characterized by intermittent joint pain. In contrast, GABAA receptors induce net excitation in advanced OA, a chronic pain state characterized by persistent ongoing joint pain. This switch is likely mediated by diminished KCC2 function in the spinal cord. Grant support from NIH Centers of Biomedical Research Excellence (COBRE) Grant P20GM103643
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