Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

Abstract

Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1␤, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.

Lentiviral vectors for gene transfer into the spinal cord glial cells

“…This suggests a function for NF-kB signaling early in the trans-synaptic spinal response to peripheral nerve injury. CCI-induced neuropathic pain is also associated with the upregulation of several proinflammatory cytokines 43,44 and, as we demonstrated, a delayed induction of iNOS. Preemptive unilateral administration of LV-srIkB into the dorsal spinal cord of the lumbar enlargement (projection site of central afferents of injured nerves) led to a complete blockade of NF-kB nuclear translocation (that is, activation of NF-kB signaling) in CCI animals.…”

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

“…Similar observations were made for GFAP labeling ( Fig 5D). We also studied the induction of cytokines classically activated by nerve injury [31,32,40,55].…”

SOCS3-Mediated Blockade of JAK/STAT3 Signaling Pathway Reveals Its Major Contribution to Spinal Cord Neuroinflammation and Mechanical Allodynia after Peripheral Nerve Injury

“…We assessed the effects of SOCS3 on JAK/STAT3 signaling and explored the consequences of this selective local blockade of JAK/STAT3 on downstream signaling responses and pain hypersensitivity in a preclinical model of neuropathic pain induced by chronic constriction injury of the sciatic nerve (CCI) in rats (Bennett and Xie, 1988). In particular, we analyzed the effects of JAK/STAT3 activity on activating transcription factor 3 (ATF3) production, which is directly related to IL-6 signaling in the spinal cord (Latrémolière et al, 2008), and CC chemokine ligand 2 (CCL2) (also called MCP-1). CCL2 plays an important role in neuroglial interactions and pathological pain (Abbadie, 2005;Thacker et al, 2009), and its expression may also be regulated by the STAT3 transcription factor (Kim et al, 2002).…”