Multiple mechanisms of microglia: A gatekeeper's contribution to pain states

Abstract

Microglia are gatekeepers in the CNS for a wide range of pathological stimuli and they blow the whistle when things go wrong. Collectively, microglia form a CNS tissue alarm system (Kreutzberg's "sensor of pathology"), and their involvement in physiological pain is in line with this function. However, pathological neuropathic pain is characterized by microglial activation that is unwanted and considered to contribute to or even cause tactile allodynia, hyperalgesia and spontaneous pain. Such abnormal microglial behavior seems likely due to an as yet ill-understood disturbance of microglial functions unrelated to inflammation.The idea that microglia have roles in the CNS that differ from those of peripheral macrophages has gained momentum with the discovery of their separate, pre-haematopoietic lineage during embryonic development and their direct interactions with synapses.

Levetiracetam synergises with common analgesics in producing antinociception in a mouse model of painful diabetic neuropathy

“…Therefore, the antinociceptive effects of ibuprofen [18,45], aspirin [40,46], and paracetamol [21,47,48] in this type of pain could be explained by their inhibition of COX-2 and ability to decrease TNF ␣ levels. It has been recently shown that ibuprofen [49], and aspirin [50] inhibit microglial activity, which could also explain their effectiveness in diabetic neuropathy, as activated microglia may be involved in the development of diabetic neuropathy [51,52]. Recent studies have suggested that the antinociception of paracetamol in neuropathic pain is mediated by cannabinoid receptors [25,53].…”

Inhibition of Mitogen-Activated Protein Kinases Phosphorylation Plays an Important Role in the Anti-nociceptive Effect of Pregabalin in Zymosan-Induced Inflammatory Pain Model

“…Spinal microglia activation (using markers CD11b and ED1) has been observed in the early phase of neuropathic pain, 2) which is closely correlated with induction and maintenance of allodynia and hyperalgesia. 3) In line with this view, microglia inhibitors successfully alleviate neuropathic pain in experimental models. 3,4) Similar with neuropathic condition, peripheral inflammation by intraplanar zymosan injection as an experimental rheumatoid arthritis model also results in the development of hyperalgesia and allodynia accompany with spinal microglia activation and cytokine expression.…”

“…3) In line with this view, microglia inhibitors successfully alleviate neuropathic pain in experimental models. 3,4) Similar with neuropathic condition, peripheral inflammation by intraplanar zymosan injection as an experimental rheumatoid arthritis model also results in the development of hyperalgesia and allodynia accompany with spinal microglia activation and cytokine expression. 5,6) Accumulative data have been revealed that activation of mitogen activated protein kinases (MAPKs, i.e., extracellular signal-regulated protein kinase (ERK) 1/2, p38 MAPK, and ERK5) in both spinal neurons and microglia may have a pivotal role in development of pain symptom following nerve injury and peripheral inflammation.…”

“…3) In neuropathic pain model, it is well documented that microglial activation (using markers CD11b and ED1) accompanying p38 phosphorylation in the spinal cord plays an important role in the development of pain. 2,4,13) Current study also revealed that zymosan dramatically increased spinal p38 phosphorylation as well as microg- lia proliferation (CD11b) and phagocytic marker (ED1) elevation in the spinal dorsal horn.…”

The endogenous cannabinoid system

“…Therefore, the interaction of neurons and microglia cells is of special importance. Microglia cells are immune cells of the central nervous system though with different functions [7]. In healthy tissue, microglia cells are in a state commonly described as the "resting state".…”