Increasing evidence suggests that T cells and glia participate in the process of neuropathic pain. However, little is known about the involvement of T cells or the interaction between glia and T cells at the molecular level. Here we investigated the phenotype of T cell infiltration into the spinal cord in inflammatory pain and explored potential crosstalk between glia and T cells. The establishment of monoarthritis produced T cell infiltration and astrocyte activation, exhibiting similar kinetics in the spinal cord. T-cell-deficient (Rag1−/−) mice significantly attenuated MA-induced mechanical allodynia and GFAP upregulation. Double immunofluorescence staining showed that CD3 mainly colocalized with interferon-gamma (IFN-γ). Western blot and flow cytometry showed that multiple intrathecal administrations of astrocytic inhibitor fluorocitrate decreased IFN-γ-production without decreasing T cell number in the spinal cord. Spinal IFN-γ blockade reduced MA-induced mechanical allodynia and astroglial activation. In contrast, treatment with rIFN-γ directly elicited persistent mechanical allodynia and upregulation of GFAP and pJNK1/2 in naïve rats. Furthermore, rIFN-γ upregulated the phosphorylation of NF-κB p65 in cultured astrocytes vitro and spinal dorsal horn vivo. The results suggest that Th1 cells and astrocytes maintain inflammatory pain and imply that there may be a positive feedback loop between these cells via IFN-γ.

To investigate the behavioral and biomolecular similarity between neuralgia and depression, a trigeminal neuralgia (TN) mouse model was established by constriction of the infraorbital nerve (CION) to mimic clinical trigeminal neuropathic pain. A mouse learned helplessness (LH) model was developed to investigate inescapable foot-shock-induced psychiatric disorders like depression in humans. Mass spectrometry was used to assess changes in the biomolecules and signaling pathways in the hippocampus from TN or LH mice. TN mice developed not only significant mechanical allodynia but also depressive-like behaviors (mainly behavioral despair) at 2 weeks after CION, similar to LH mice. MS analysis demonstrated common and distinctive protein changes in the hippocampus between groups. Many protein function families (such as cell-to-cell signaling and interaction, and cell assembly and organization,) and signaling pathways (e.g., the Huntington's disease pathway) were involved in chronic neuralgia and depression. Together, these results demonstrated that the LH and TN models both develop depressive-like behaviors, and revealed the involvement of many psychiatric disorder-related biomolecules/pathways in the pathogenesis of TN and LH.

Background and Purpose Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia‐mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia‐induced anxiodepression remains unclear. Experimental Approach Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive‐like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia. Key Results Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up‐regulated ipsilateral hippocampal ATP and interleukin‐1β (IL‐1β) levels, impaired ipsilateral hippocampal long‐term potentiation (LTP) and induced anxiodepressive‐like behaviours in a time‐dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia‐induced anxiodepressive‐like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia‐induced microglial activation and anxiodepressive‐like behaviours. Furthermore, we demonstrated that microglia‐derived IL‐1β mediated microglial activation‐induced anxiodepressive‐like behaviours and LTP impairment. Conclusion and Implications These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain‐related anxiodepressive‐like behaviours via IL‐1β. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia‐induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia‐related anxiety and depressive disorder.

Patients suffering from trigeminal neuralgia (TN) are often accompanied by anxiety and depression. Whether and how microglia are involved in TN-induced anxiodepressive remains unclear. Here, we unconventionally report that TN activities ipsilateral but not contralateral hippocampal microglia, upregulates ipsilateral hippocampal ATP and interleukin1β (IL-1β) levels, impairs ipsilateral hippocampal long-term potential (LTP), and induces anxiodepressive-like behaviros in a time-dependent manner in rodents. Specifically, activation of ipsilateral hippocampal microglia is necessary for TN-induced anxiodepressive-like behaviors; and unilateral activating hippocampal microglia is sufficient to elicit an anxiodepressive state and impair LTP. Knockdown of ipsilateral hippocampal P2X7 receptor prevented TN-induced microglia activation and anxiodepressive-like behaviors. Furthermore, we demonstrate that microglia-derived IL-1β mediates microglia activation-induced anxiodepressive-like behaviros and LTP impairment. Together, these findings suggest that priming of microglia with ATP/P2X7R in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviros via IL-1β. Our results also reveal an asymmetric role of the bilateral hippocampus in TN-induced anxiety and depression.