It is realized that the immune system plays an important role in the irritation of pain. Many researches try to explain the development of pain. Some mechanisms of neuropathic pain include peripheral mechanisms: (1) ectopic discharges and ephaptic conduction, (2) collateral sprouting, (3) coupling between the sympathetic nervous system and the sensory nervous system, (4) bradykinin; and central mechanisms: (1) spinal cord-anatomical re-organization, (2) spinal cord-hyperexcitability, (3) endogenous opioid and cannabinoid systems.2
Many studies concentrate on the role of immune factors in the occurrence of pain. For TNF, IL-1, IL-6, NGF and prostaglandin E2 (PGE2), there is considerable evidence that they are present in inflammatory exudates; they can produce pain or hyperalgesia when irritants are exogenously administered to animals and humans; and, most importantly, antagonism or neutralization of these factors reduces pain and hyperalgesia in many animal models of inflammation (as below). Thus, these cytokines can be both necessary and sufficient for pathogen-induced hyperalgesia to occur. Bennett30 reported a new model of inflammation in which a focal neuritis was produced in the rat sciatic nerve. The result suggested the presence of a neuroimmune interaction that occurs at the onset of nerve injury and contributes to the development of neuropathic pain. Hyperalgesia is produced both by intraperitoneal administration of the cell walls of gram-negative bacteria (endotoxin; also called lipopolysaccharide)31 and by intraperitoneal live bacteria,32 both of which are known to elicit the release of proinflammatory cytokines from a variety of immune cells.
Shu et al33, the first to describe the link between NGF and pain, presented the results of experiments performed in their laboratory, identified the mechanisms underlying the initial hyperalgesic response to NGF. The initial hyperalgesia in response to systemic or peripherally administered NGF depends on indirect mechanisms, specifically mast cell degranulation. They presented recent evidence indicating that NGF also is capable of potentiating capsaicin-evoked currents in isolated sensory neurons. Utilizing this intriguing observation, they presented a model that would account for the initial NGF-induced thermal hyperalgesia. Other studies are trying to explain the algesic effects of NGF.8 They found that the high-affinity NGF receptors (tyrosine kinase receptor A, TrkA) were expressed by about 50% of nociceptors and their activation led to phosphorylation and sensitization of TRPV1 receptors, which might account for NGF-induced heat hyperalgesia. Another important action of NGF is its modulation of nociceptor gene expression such as TRPV1, P2X3, Nav 1.8, brain- derived neurotrophic factor (BDNF) and substance P after retrograde transport of NGF-TrkA to the nucleus, which might underlie increases in long-term nociceptor sensitivity.
Thompson et al34 summarized a growing part of data implicating a critical role for brain derived neurotrophic factor in the altered nociceptive processing observed in the presence of inflammation. Brain derived neurotrophic factor appears to function as a neurotransmitter/neuromodulator in the dorsal horn of the spinal cord, where it is released from the central terminals of small-caliber afferents and increases the excitability of dorsal horn neurons.
NO is an important mediator of hyperalgesia and induced in inflamed tissues, probably through both inducible and neuronal nitric oxide synthase (iNOS and nNOS, respectively).35 NO donors can induce pain in humans36 and NOS inhibitors can reduce inflammatory hyperalgesia in a PGE2-dependent manner.37 Antagonism of each of the mediators described above produces substantial anti- hyperalgesia with high efficacy of pain relief.
TNF is considered to be the prototype in the family of pro-inflammatory cytokines. It initiates a cascade of activation of cytokines and growth factors (for example, NGF, NO and PGE2). There is considerable evidence for its involvement in neuropathic pain. Several studies have shown a correlation between the level of TNF expression and the development of allodynia or hyperalgesia in neuropathic pain models.38,39 The development of allodynia or hyperalgesia can be increased by the endoneurial administration of TNF, whereas antagonism of TNF has the opposite effect.40-42 Benett43 looked into the contribution of the inflammatory response alone on the production of neuropathic pain. He found that using a specific inhibitor of the synthesis of TNFα or cyclosporin-A (a broad-spectrum immunosuppressor) will reduce the response to neuropathic pain. In recent years, the importance of TNF in pain relief has been underscored by the tremendous success of TNF antibodies or neutralizing reagents for the treatment of many autoimmune disorders, including psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and rheumatoid arthritis.44,45 TNF might also act directly on TNF receptors that are expressed by nociceptors to produce sensitization.40 Nerve injury also leads to increased expression of TNF receptors 1 and 2 by damaged sensory neurons.46 Finally, pre-emptive (but not delayed) treatment with etanercept (a TNF-sequestering drug) can inhibit mechanical allodynia in neuropathic models, which indicates that TNF is particularly important in the initiation of neuropathic pain.40,47
IL-1 is a potent pro-inflammatory cytokine that is involved in neuropathic pain. Intrathecal administration of IL-1 can lead to symptoms of neuropathic pain in healthy rats.48 The expression of IL-1 is upregulated after nerve injury, and neutralizing antibodies to IL-1 receptors reduce pain-associated behaviours in mouse models of neuropathy.49 However, the mechanism of action of IL-1 in the periphery is unclear. Several studies indicate that the mechanism might be involved in a complex signaling cascade that leads to the production of pronociceptive compounds (NO, NGF, prostaglandins, etc.) from immune cells or Schwann cells. IL-1 might also directly excite nociceptive fibres50 or increase their responses to heat stimuli through an IL-1 receptor type I (IL-1RI)/protein tyrosine kinase (PTK)/protein kinase C (PKC)-dependent mechanism.51 Hyperalgesia can be elicited simply by administering either IL-1 or TNF alone;21,22 and the key importance of proinflam- matory cytokines in pathogenic hyperalgesia is clear from the fact that it can be blocked by either an IL-1 receptor antagonist or TNF binding protein.21,52
There are many studies investigating the role of IL-6 in the development of pain53-55 and it is well reviewed56 that IL-6 related to the development of pain and intrathecal anti-IL-6 antibody, otherwise, will attenuate this reaction. Mechanical allodynia is correlated with the levels of IL-6 immunoreactivity or mRNA in the sciatic nerve and DRG, respectively, after nerve constriction injury. Compared with wild-type mice, thermal hyperalgesia and mechanical allodynia were less in IL-6-knockout mice.57 The mechanism of IL-6 action is still not well established.
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