JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat

Abstract

Peripheral nerve lesion leads to the production of interleukin 6 (IL‐6)‐related neuropoietic cytokines involved in nerve protection and regeneration. This family of cytokines mainly signal through the signal transducer and activator of transcription (STAT) pathway that is locally activated in injured nerves. IL‐6 is also involved in pain that frequently arises from peripheral nerve lesion. We investigated the possible activation of this major IL‐6 signaling system in the spinal cord after peripheral nerve injury and its role in neuropathic pain. Ligation of L5–L6 spinal nerves (SNL) evoked an accumulation of active, phosphorylated form of STAT3 in microglial cells of dorsal spinal cord mostly in projection areas of injured nerves. SNL resulted also in a massive induction of IL‐6 mRNA expression in dorsal root ganglia and increased concentration of IL‐6 in dorsal spinal cord. Intrathecal injection of anti‐rat IL‐6 antibodies prevented the SNL‐induced accumulation of phospho‐STAT3 in the spinal cord. STAT3 pathway blockade with Janus kinase 2 inhibitor AG490 attenuated both mechanical allodynia and thermal hyperalgesia in SNL rats. These data show that in response to SNL injury Janus kinase/STAT3 system is activated mainly through IL‐6 signaling in spinal microglia and that this transduction pathway participates in development of pain associated with nerve alteration.

Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression

“…This raises the possibility that concurrent treatment of both pain and depression might be possible through regulation of brain IDO activity, in contrast to the current approach of symptomatic management using antidepressants and analgesics (3). Although the neural and cellular mechanism underlying the interaction between pain and depression is likely to be complex and involves other neurotransmitters and neuromodulators (25)(26)(27)(28)(29)(30)(31)(32)(33), the present findings may suggest a new strategy of clinical intervention. This new strategy focuses on both prevention and reversal of comorbid interactions between pain and depression by targeting its underlying mechanism involving altered ratios of endogenous tryptophan metabolites resulting from upregulated IDO expression in certain brain regions.…”

Physiology of Microglia

“…This system was reported to be activated after a peripheral nerve injury and may contribute to development of mechanical allodynia and neuropathic pain (223).…”

Anti-hyperalgesic effects of AG490, a Janus kinase inhibitor, in a rat model of inflammatory pain

“…Additionally, in the mechanical hyperalgesia test, AG490 treatment increased the PWT at all doses tested; however, this effect was not statistically significant. Therefore, we speculate that AG490 is more effective at reducing mechanical allodynia as measured in previous studies (5,6), than for reducing mechanical hyperalgesia, as shown in the present study. It is also possible that differences in animal model, and route and dose of AG490 administration influence the effects of AG490 on the response to mechanical stimuli.…”

“…in a volume of 100 µl. As reported earlier, the in vivo pharmacological effects of AG490 were observed 4 h after treatment (5,6). Thus, the behavioral tests were performed before (baseline assessment) and 4 h after treatment.…”