The bilateral joint-brain connection:pain mechanisms and neuronal control of inflammation

Major neuronal mechanisms of inflammatory joint pain are the peripheral and spinal sensitization. We addressed the role of proinflammatory cytokines in neuronal sensitization. A single injection of either TNF-α, interleukin-6, interleukin-1 β and interleukin-17 into the knee joint induced a slowly developing and long-lasting mechanical sensitization of the neurons mimicking longlasting inflammation-evoked sensitization. Vice versa the neutralization of these cytokines reduced hyperalgesia in antigen-induced arthritis. Neutralization of TNF-α significantly reduced mechanical and thermal hyperalgesia, neutralization of IL-1β reduced thermal hyperalgesia, neutralization of IL-17 reduced in particular mechanical hyperalgesia. Neutralization of IL-6 reduced mechanical hyperalgesia upon pretreatment. Spinal cytokines can contribute to inflammation-evoked spinal hyperxcitability. In particular IL-6 was rapidly increased in the spinal cord upon joint inflammation, and neutralization of IL-6 attenuated the development of spinal hyperexcitability. However, the nervous system also influences the inflammatory process. In antigen-induced arthritis in mice chemical sympathectomy or β-adrenergic blockers significantly reduced the magnitude of the acute phase of inflammation. Furthermore, neutralization of spinal TNF-α decreased the inflammatory process in the knee joint. These data suggest that the expression of inflammation is partly dependent on neuronal reflexes.