Fig. 5

Overview of pain transmission in the knee joint. a Synaptic interface between primary afferent nociceptors and second-order neurons in the spinal dorsal horn. b Connectivity patterns and regional distribution of nociceptors and second-order neurons in the spinal cord. c Neuronal pain signaling pathway. d Magnified peripheral nociceptor terminals showing Nav and TRP channel cooperation with NGF to initiate pain signaling during noxious chemical and mechanical stimulation. e The distribution of nociceptors at the periphery. The cell bodies of nociceptors cluster in the DRG, where each nociceptor extends two axons: one toward the periphery and the other to the dorsal horn of the spinal cord. At the periphery, nociceptor terminals transduce mechanical or chemical stimuli, including proinflammatory cytokines, inflammatory mediators such as those released from dysfunctional organelles, and mitochondrial ROS (mtROS), into pain signals via Ca²⁺/Na⁺ influx through TRP and Na_v channels. Under inflammatory conditions, NGF secreted by Møs, MCs, and FLSs synergizes with cytokines and mtROS to increase TRP/Na_v sensitization and SP expression, amplifying nociceptive signaling. Pain signals are transmitted to second-order spinal neurons through synaptic neurotransmitter release and then relayed to the brain for perceptual processing. AP action potential, SP substance P, ER endoplasmic reticulum, mtROS mitochondrial ROS, Mø macrophage, MC mast cell, FLS fibroblast-like synoviocyte, TRP transient receptor potential channel, Na_v voltage-gated sodium channel