Abstract
BackgroundThere is a growing body of evidence that unilateral nerve injury induces bilateral response, the mechanism of which is not exactly known. Because cytokines act as crucial signaling molecules for response of peripheral nerves to injury, they may be induced to mediate the reaction in remote structures.MethodsWe studied levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) proteins using ELISA in the ipsilateral and contralateral lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) from naïve rats, rats operated on to create unilateral chronic constriction injury (CCI) of the sciatic nerve, and sham-operated rats. Withdrawal thresholds for mechanical allodynia and thermal hyperalgesia were measured in the ipsilateral and contralateral hind and forepaws.ResultsThe ipsilateral hind paws of all rats operated upon for CCI displayed decreased withdrawal thresholds for mechanical allodynia and thermal hyperalgesia, while no significant behavioral changes were found in the contralateral hind paws and both forepaws. Significantly lower baseline levels of TNF-α and IL-10 protein were measured by ELISA in the lumbar than cervical DRG of naïve rats. Bilateral elevation of TNF-α was induced in both the lumbar and cervical DRG by unilateral CCI of the sciatic nerve for 7 and 14 days, while the level of IL-10 protein was increased bilaterally in the lumbar DRG 1 and 3 days after operation. IL-10 levels declined bilaterally even below baseline level in both cervical and lumbar DRG 7 days from CCI and normalized after 14 days. In contrast to no significant changes in TNF-α, level of IL-10 protein was significantly increased in the ipsilateral lumbar DRG after 3 days and bilaterally in the lumbar DRG after 14 days from sham operation.ConclusionsThe results of our experiments show a bilateral elevation of TNF-α and IL-10 not only in the homonymous DRG but also in the heteronymous DRG unassociated with the injured nerve. This suggests that bilaterally increased levels of TNF-α and IL-10 in DRG following unilateral CCI are linked with general neuroinflammatory reaction of the nervous system to injury rather than only to development and maintenance of neuropathic pain.
Highlights
There is a growing body of evidence that unilateral nerve injury induces bilateral response, the mechanism of which is not exactly known
tumor necrosis factor α (TNF-α) protein level following constriction injury (CCI) and the sham operation (Figure 2A) L4-L5 dorsal root ganglia (DRG) Despite the unilateral CCI of the sciatic nerve, the level of TNF-α protein remained close to the baseline level in L4L5 DRG of both sides for 1 and 3 days after operation
The peak values were measured after 7 days, when the level of TNF-α protein was more than four times higher in the ipsi- and contralateral L4-L5 DRG than in those from the naïve rats
Summary
There is a growing body of evidence that unilateral nerve injury induces bilateral response, the mechanism of which is not exactly known. Because cytokines act as crucial signaling molecules for response of peripheral nerves to injury, they may be induced to mediate the reaction in remote structures. Peripheral neuropathic pain, manifested by spontaneous pain, hyperalgesia and allodynia, arises as a result of various types of nerve damage, e.g., diabetic neuropathy, HIV neuropathy, post-herpetic neuralgia, drug-induced neu-. Neuropathic pain usually arises from the area innervated by the damaged nerve, there has been increasing evidence that a peripheral nerve lesion affects the contralateral non-lesioned side [6]. Cytokines play a crucial role in the nervous system's reaction to injury. These are signaling proteins that serve as intercellular messengers in immune reaction to injury of the nervous system [8,9]. Blockade of proinflammatory cytokines and/or administration of anti-inflammatory cytokines have reduced neuropathic hyperalgesia in animal models [13,14,15,16]
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