The Molecular Mechanisms Underlying The Involvement Of Spinal IL-23 And IL-23R In Rat Neuropathic Pain

Activation of glia in the spinal cord is a key process in the development of pathological pain. IL-23, a member of IL-12 family, is expressed in the glia and involved in the glial activation. Accumulating evidence manifests that IL-23 plays a key role in Multiple Sclerosis (MS), with which about 80% patients are suffered from chronic pain. Therefore, it is reasonable to hypothesize that in the spinal cord, IL-23 is an essential participator in the activation of glia and the development of pathological pain.To verify the hypothesis, the role of IL-23 in the TSS (Tetanic stimulation of the sciatic nerve)-induced neuropathic pain was investigated.The results show that:(1) in the spinal cord, both of IL-23 and IL-23R are expressed in astrocyte, and upregulated after TSS; (2) the TSS-induced allodynia is relieved by pre-blockade of the IL-23/IL-23 R signal; (3) allodynia is induced in naive rats by intrathecal application of exogenous IL-23.It is proved that the expression of IL-23 is modulated by the CX3CL1/CX3CR1 signal, and CX3CL1/CX3CR1 signal, in the spinal cord, plays an important role in the activation of microglia and the pathological pain. For the further investigation, CX3CL1/CX3CR1 signal is chose to be the next target.In the current experiments, it is demonstrated that:(1) the expression of IL-23/IL-23R is regulated by CX3CL1/CX3CR1 signal, down-regulated in the TSS rats by pre-blockade of the CX3CL1/CX3CR1 signal, up-regulated in the naive rats by intrathecal application of exogenous CX3CL1; (2) Both of CX3CL1 and CX3CR1 proteins were obviously increased after TSS; (3) the TSS-induced allodynia is relieved by pre-blockade of the CX3CL1/CX3CR1 signal, and allodynia is induced in naive rats by intrathecal application of exogenous CX3CL1; (4) in the spinal cord, CX3CL1 mainly expressed in neuron and astrocyte, and CX3CR1 expressed in microglia.The Spinal CX3CL1/CX3CR1 signal is initiated in microglia, and both of IL-23 and IL-23R are expressed in astrocyte. Consequently, the IL-23/IL-23R signal may be indirectly regulated by the CX3CL1/CX3CR1 signal. The regulation is proposed to be mediated by IL-18/IL-18R signal, by which the interaction between microglia and astrocyte is mediated.The results show that:(1) in the spinal cord IL-18 and IL-18R are respectively expressed in the microglia and the astrocyte, and both of them are upregulated by TSS; (2) the expression of IL-23/IL-23R signal is regulated by IL-18/IL-18R signal, down-regulated in the TSS rats by pre-blockade of the IL-18/IL-18R signal, up-regulated in the naive rats by intrathecal application of exogenous IL-18; (3) the TSS-induced allodynia is relieved by pre-blockade of the IL-18/IL-18R signal, and allodynia is induced in naive rats by intrathecal application of exogenous IL-18; (4) the expression of IL-18/IL-18R signal is regulated by CX3CL1/CX3CR1 signal, down-regulated in the TSS rats by pre-blockade of the CX3CL1/CX3CR1 signal, up-regulated in the naive rats by intrathecal application of exogenous CX3CL1.In conclusion, our present study demonstrated that spinal cord IL-23/IL-23R signal is involved in the TSS-induced neuropathic pain, and the regulation of CX3CL1/CX3CR1 on IL-23/IL-23R signal is mediated by IL-18/IL-18R signal.