Figure 1.

Neuroanatomy of the pain pathway and analgesic targets in OA. a | Pain signals are detected by nociceptors in the periphery and carried to the dorsal horn of the spinal cord. Various analgesics that are efficacious against joint pain act in the periphery by targeting receptors expressed at nociceptor peripheral terminals. b | The central terminals of the afferent nociceptors synapse with second-order neurons in the dorsal horn, in a stratified pattern that is anatomically very precisely organized. Second-order neurons are either interneurons (not shown) or projection neurons that cross to the contralateral side and carry the signal up the spinal cord. Central sensitization can occur through the strengthening of synapses and through the loss of inhibitory mechanisms. In addition, the activation of microglia contributes to enhanced pain sensitivity. Prostaglandins can also have a sensitizing effect in the dorsal horn, and NSAIDs can thus exert central analgesic actions, in addition to their peripheral actions. Opioids can inhibit incoming pain signals in the dorsal horn. c | Projection neurons relay pain signals along the spinothalamic tract to the thalamus, and along the spinoreticulothalamic tract to the brainstem. From there, the signals can be propagated to different areas of the brain, including the cortex. Descending pathways (black arrows), both facilitating and inhibitory, modulate pain transmission; descending inhibitory pathways release noradrenaline and serotonin onto the spinal circuits. SNRIs engage these descending inhibitory pathways. RVM neurons are opioid sensitive, and morphine has an analgesic effect through engaging descending inhibition. Abbreviations: Amy, amygdala; DRG, dorsal root ganglion; GPCR, G-protein-coupled receptor; HP, hippocampus; NAc, nucleus accumbens; NGF, nerve growth factor; PAG, peri-aqueductal grey; PG, prostaglandin; RVM, rostral ventromedial medulla; SNRI, serotonin–noradrenaline reuptake inhibitor.