Fig. 4

Schematic illustration showing how intra-articular inflammatory mediators are delivered to the posterior horn of the spinal cord and finally cause pain sensitization. The nociceptive stimuli signals are transmitted to the posterior horn of the spinal cord through A fibers and C fibers, leading to increased Cacna2d1 channel activity. The increased influx of Ca²⁺ further triggers a calcium-sensitive cascade, releasing pain neurotransmitters (Vglut2, SP, and c-fos). Neurons have higher excitability under the long-term infiltration of inflammatory mediators and pain neurotransmitters, which increases Ca²⁺ influx and continuously releases pain neurotransmitters forming a vicious cycle reaction, leading to hyperalgesia