Experimental neurology
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Experimental neurology · Apr 2012
ReviewEmerging role of microglial kinin B1 receptor in diabetic pain neuropathy.
Nowadays diabetes mellitus has reached epidemic level and is considered as the primary cause of foot amputation and pain neuropathy. The classical theories explaining the development of diabetic pain neuropathy include the imbalance of neuronal biochemical pathways (Polyol pathway, Na(+)/K(+) ATPase pump, AGE, ROS) and microangiopathy which promote nerve fibers depolarization, sensitization, ectopic discharges, demyelization and ultimately neuronal death. However, the current pharmacotherapy targeting those pathways brings variable, not always satisfactory and temporal relief in patients experiencing diabetic pain neuropathy. ⋯ A few selective B1R antagonists have been fully characterized in animal models although small molecules orally active are urgently needed for targeting human B1R on CNS microglia. Thus far, the pharmacological blockade of kinin B1R in various animal paradigms or its genetic deletion in B1R knock-out mice failed to cause unwanted side effects, making this approach feasible. This is consistent with the highly inducible feature of this atypical G-protein coupled receptor whose expression can be seen as the alarming signature of immune and inflammatory diseases, notably diabetes mellitus.
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Experimental neurology · Apr 2012
ReviewMultiple mechanisms of microglia: a gatekeeper's contribution to pain states.
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. ⋯ 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-hematopoietic lineage during embryonic development and their direct interactions with synapses.
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Experimental neurology · Apr 2012
ReviewPropentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages.
There is a growing body of preclinical evidence for the potential involvement of glial cells in neuropathic pain conditions. Several glial-targeted agents are in development for the treatment of pain conditions. Here we report the failure of a glial modulating agent, propentofylline, to decrease pain reported in association with post-herpetic neuralgia. ⋯ Overall, human microglia were less responsive to LPS stimulation and propentofylline treatment than the other cell types. Our data demonstrate significant functional differences between cell types and species following propentofylline treatment and LPS stimulation. These results may help explain the differential behavioral effects of propentofylline observed between rodent models of pain and the human clinical trial.
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Experimental neurology · Apr 2012
ReviewPurinergic systems, neuropathic pain and the role of microglia.
We have learned various data on the role of purinoceptors (P2X4, P2X7, P2Y6 and P2Y12) expressed in spinal microglia and several factors that presumably activate microglia in neuropathic pain after peripheral nerve injury. Purinergic receptor-mediated spinal microglial functions make a critical contribution to pathologically enhanced pain processing in the dorsal horn. Microglial purinoceptors might be promising targets for treating neuropathic pain. A predicted therapeutic benefit of interfering with microglial purinergic receptors may be that normal pain sensitivity would be unaffected since expression or activity of most of these receptors are upregulated or enhanced predominantly in activated microglia in the spinal cord where damaged sensory fibers project.
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This special issue of Experimental Neurology is devoted to the role of Microglia and Chronic Pain. Chronic pain affects 116 million people per year in the United States, which is more than heart disease, cancer, and diabetes combined. Nervous system trauma and disease are principal contributors to the establishment of chronic pain in people and in animal models. ⋯ Once considered to function solely as the phagocytotic cells of the CNS, more recent work has demonstrated that persistent activation of the microglial population may contribute to continued dysfunction including chronic pain. In the invited articles for this special issue on Microglia and Chronic Pain, we present evidence for the role of persistent microglial activation in chronic pain after peripheral and central nervous system injury, as well as in diabetic pain, post-herpetic neuralgia pain and related diseases. Collectively, the body of work indicates the importance of understanding the roles of microglial cells in chronic pain which will lead to targeted treatment to attenuate or alleviate chronic neuropathic pain syndromes.