Chemogenetic and pharmacological activation of the oxytocin system ameliorates adjuvant arthritis in rats

Oxytocin (OXT) is an endogenous neuropeptide involved in the regulation of nociceptive processing and inflammatory responses. Chronic inflammatory arthritis is characterized by persistent inflammation and pain, and understanding neuroendocrine mechanisms that regulate both processes may provide new insights into the pathophysiology of chronic inflammatory pain. Previous studies have shown that endogenous OXT has both anti-inflammatory and antinociceptive effects, suggesting that activation of the OXT system may influence arthritis by modulating inflammatory and pain-related pathways. However, whether activation of endogenous OXT signaling can modulate the progression of chronic inflammatory arthritis and its associated pain remains incompletely understood. Therefore, this study investigated whether chemogenetic activation of OXT neurons and pharmacological stimulation of OXT receptors modulate disease progression and pain-related outcomes in a rat model of adjuvant arthritis. Adjuvant arthritis was induced in adult male OXT-hM3Dq-mCherry transgenic rats (n = 39) and adult male Wistar rats (n = 10). The transgenic rats were treated with CNO, whereas Wistar rats were treated with LIT-001, with the corresponding vehicle-treated groups serving as controls. Arthritis severity, ankle swelling, mechanical hypersensitivity, joint histopathology, and neuronal activity markers were evaluated. Chemogenetic activation of OXT neurons attenuated arthritis progression during both the onset phase (Days 10-12) and established phase (Days 15-17). During the onset phase, it also reduced ankle swelling and prevented the decline in mechanical nociceptive thresholds. Descriptive histological evaluation showed less pronounced inflammatory cell infiltration, synovial hyperplasia, pannus formation, cartilage destruction, and bone erosion in affected joints. Similarly, repeated administration of the oxytocin receptor agonist LIT-001 ameliorated arthritis severity, joint swelling, and inflammatory pain-related behaviors. Immunohistochemical analyses further revealed increased FosB expression in the paraventricular nucleus and reduced numbers of FosB-immunoreactive and tryptophan hydroxylase (TPH)-immunoreactive cells in the dorsal raphe nucleus following LIT-001 treatment. These findings show that chemogenetic activation of endogenous OXT neurons and administration of the OXT receptor agonist LIT-001 ameliorate arthritis pathology and inflammatory pain-related behaviors in adjuvant arthritis. The OXT system may therefore contribute to the regulation of chronic inflammatory arthritis through coordinated effects on peripheral inflammation and central pain processing.