Pain is presented as one of many natural consequences of peripheral infection and injury. Immune reaction is generally initiated by peripheral infection and injury, including exposure to microbial cell wall fragments or toxins, irritant chemicals and autoimmune reaction or neuropathy. The constellation of changes that results from such immune challenges is so called the sickness response, including physiological responses (fever, alterations in plasma ions to suppress minerals required by bacteria/viruses to replicate, increases in white blood cell replication, increased sleep, etc.), behavioral responses (decreased social interaction and exploration, decreased sexual activity, decreased food and water intake, etc.), and hormonal responses (increased release of classic hypothalamo-pituitary-adrenal and sympathetic hormones).
The sickness response results from immune-to-brain communication initiated by proinflammatory cytokines released by activated immune cells. As a group, these proinflammatory cytokines include nerve growth factor (NGF), nitric oxide (NO), prostanoids, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Neutrophils are the earliest inflammatory cells infiltrating tissues from the blood. Perkins et al7 found that neutrophils could invade into the damaged nerve and produced various inflammatory factors including lipoxygenase products, NO, cytokines, and chemokines. NGF is a well-established inflammatory mediator,8 of which the hyperalgesic action seems to depend, in part, on neutrophil accumulation.9,10 In damaged peripheral nerves, as in other tissues, macrophages are recruited by chemotactic molecules. Macrophages can release many inflammatory mediators, notably pro-inflammatory cytokines (TNFα, IL-1β), NGF, NO and prostanoids. Moreover, IL-1 will in turn upregulate the synthesis of a range of potent molecules including NGF and TNF during Wallerian degeneration by Schwann cells.11 Zuo et al12 found that mast cells were activated in model of partial sciatic nerve injury. T and B cells can also generate inflammatory cytokines and chemokines, and contribute to innate immune responses. Moalem et al13 characterized T-cell infiltration into injured sciatic nerves in a neuropathic mode. The mediators produced by immune cells may be necessary and sufficient for sickness since preventing their actions by receptor antagonists can block sickness responses, whereas exogenous administration of these proteins can create sickness response.14
Some investigators15,16 believe that the expression of proinflammatory cytokines is related to the activation of nuclear factor-κB (NF-κB). The NF-κB signal transduction pathway mediates expression of a certain number of genes that participate in inflammatory and immune processes,17 including IL-1, IL-6, IL-8, TNFα, dynorphin, ICAM, VCAM, etc. Trauma will stimulate the nuclear translocation of NF-κB, activate this transcription factor,18 thus promote the expression of immune factors. Inhibition of the nuclear translocation of NF-κB will attenuate the pain that induced by dynorphin.15