Table 1.
Recent findings of microglial signaling in CPSP mediation.
| Cellular targets | Key findings | References |
|---|---|---|
| Purinergic receptors | ||
| * (1) P2X4 | Intra-thalamic injection of autologous blood leads to the mechanical allodynia and the expression of P2X4 within the microglia of peri-lesion tissues. Either P2X4 blocker or adrenergic antidepressants and antiepileptics reverses the pain behavior. | Lu 30 |
| (2) P2X7 | Knockout P2X7 suppresses thermal and mechanical pain behavior induced by intra-thalamic injection of type IV collagenase, which are accompanied with lower expression of thalamic GFAP, Iba1 and BDNF, as well as increased intracellular [Cl−], compared to wild type mice. TH-lesioned tissue generates the high amount of ATP, which promotes microglial IL-1β release via acting on P2X7 receptors. IL-1β further enhances neuronal glutamate release, resulting in a higher frequency of neuron bursting in response to nociceptive stimulation. |
Huang
33
Kuan 15 |
| (3) Panx-1 | TH induces Panx-1 channel opening on microglia cell membrane within the peri-lesion area, which promotes the release of pro-inflammatory factors, and eventually induces pain behavior. | Bu 36 |
| Chemotactic factors | ||
| (4) (5) SDF-1 | At the acute phase of TH, HIF-1α level is increased in the microglial cytoplasm of peri-lesion tissue. HIF-1 complex binds to HRE in the DNA sequence and then induces either SDF-1 or CXCR-4 expression. At the late phase of TH, released SDF-1 acts on functional CXCR-4 through autocrine and paracrine pathway, which results in the release of pro-inflammatory cytokines, and subsequently increase neuronal excitation. TH induces abnormal activation of microglia and the elevation of SDF-1 and CXCR-4 at the spinal dorsal horn. Intrathecal administration of microglial and CXCR-4 inhibitors blocks the expression of SDF-1 and CXCR-4, as well as mechanical pain hypersensitivity. |
Yang
17
Liang 41 |
| (6) MCP-1 | The expression of MCP-1 was increased within the neurons of spinal dorsal horn throughout the acute phase and late phase after TH. Neutralizing MCP-1 by antibodies alleviates spinal microglial activation and pain behavior. | Yang 43 |
| Inflammatory mediators | ||
| (7) HMGB-1 | Cerebral ischemia stimulates the secretion of HMGB-1 protein from spinal neurons. At the acute phase of stroke, neutralizing HMGB-1 or antagonizing TLR-4 prevented microglial depolarization, NOS activity and mechanical allodynia. In addition, pharmacological inhibition of NOS also causes an analgesic effect in mice. | Matsuura 45 |
| (8) HIF-1α | TH induces microglial depolarization, HIF-1α expression, the construction of inflammasome NLRP-3 and pro-inflammatory factors release within thalamic injury region. These effects as well as pain behavior can be reversed by genetic deletion of HIF-1α. | Shi 46 |
| Kinases and others | ||
| (9) FGR | At the acute phase of TH, microglial FGR was transcriptionally upregulated, which promotes TNF-α production via activating NF-κB–ERK1/2 signaling pathway. These effects as well as hyperalgesia can be abolished by either knock down or pharmacological inhibition of FGR. | Huang 49 |
| (10) BDNF | At the late phase after TH, the ATP released by lesion tissue act on microglial P2X4 receptor, which caused BDNF production. Released BDNF over-bound TrkB receptors of thalamic neurons, which induced downstream inhibition of KCC2 and GABA receptors, and consequently enhanced neuronal activity in response to nociceptive inputs. | Shih 16 |
*
Annotation: the numbers in parentheses are used to direct the signaling in Figure 2.