Abstract
BackgroundCurrent research implicates interleukin (IL)-6 as a key component of the nervous-system response to injury with various effects.MethodsWe used unilateral chronic constriction injury (CCI) of rat sciatic nerve as a model for neuropathic pain. Immunofluorescence, ELISA, western blotting and in situ hybridization were used to investigate bilateral changes in IL-6 protein and mRNA in both lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) following CCI. The operated (CCI) and sham-operated (sham) rats were assessed after 1, 3, 7, and 14 days. Withdrawal thresholds for mechanical hyperalgesia and latencies for thermal hyperalgesia were measured in both ipsilateral and contralateral hind and fore paws.ResultsThe ipsilateral hind paws of all CCI rats displayed a decreased threshold of mechanical hyperalgesia and withdrawal latency of thermal hyperalgesia, while the contralateral hind and fore paws of both sides exhibited no significant changes in mechanical or thermal sensitivity. No significant behavioral changes were found in the hind and fore paws on either side of the sham rats, except for thermal hypersensitivity, which was present bilaterally at 3 days. Unilateral CCI of the sciatic nerve induced a bilateral increase in IL-6 immunostaining in the neuronal bodies and satellite glial cells (SGC) surrounding neurons of both lumbar and cervical DRG, compared with those of naive control rats. This bilateral increase in IL-6 protein levels was confirmed by ELISA and western blotting. More intense staining for IL-6 mRNA was detected in lumbar and cervical DRG from both sides of rats following CCI. The DRG removed from sham rats displayed a similar pattern of staining for IL-6 protein and mRNA as found in naive DRG, but there was a higher staining intensity in SGC.ConclusionsBilateral elevation of IL-6 protein and mRNA is not limited to DRG homonymous to the injured nerve, but also extended to DRG that are heteronymous to the injured nerve. The results for IL-6 suggest that the neuroinflammatory reaction of DRG to nerve injury is propagated alongside the neuroaxis from the lumbar to the remote cervical segments. This is probably related to conditioning of cervical DRG neurons to injury.
Highlights
Current research implicates interleukin (IL)-6 as a key component of the nervous-system response to injury with various effects
There is compelling evidence indicating that hyperalgesia and ongoing pain due to peripheral nerve injury are associated with excitability of [4] and cellular and molecular changes in dorsal root ganglia (DRG), including proliferation and activation of satellite glial cells (SGC) [5], invasion of macrophages [6], and upregulation and downregulation of genes and proteins [7,8]
Behavioral tests All rats with constriction injury (CCI) of the sciatic nerve displayed decreased thresholds of mechanical hyperalgesia and withdrawal latencies of thermal hyperalgesia restricted to the hind paws ipsilateral to nerve ligatures as signs of neuropathic pain
Summary
Current research implicates interleukin (IL)-6 as a key component of the nervous-system response to injury with various effects. Peripheral neuropathic pain, manifested as spontaneous pain and hyperalgesia, arises as a result of various forms of peripheral nerve damage, such as traumatic nerve injury, or neuropathy associated with diabetes or HIV infection [2,3]. There is compelling evidence indicating that hyperalgesia and ongoing pain due to peripheral nerve injury are associated with excitability of [4] and cellular and molecular changes in dorsal root ganglia (DRG), including proliferation and activation of satellite glial cells (SGC) [5], invasion of macrophages [6], and upregulation and downregulation of genes and proteins [7,8]. A growing body of evidence implicates IL-6 as a key component in the response of the nervous system to injury. IL-6 is involved in promoting neuronal survival and protection against neuronal damage [11,12] and in modulating pain [13,14]
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