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Presynaptic mGluR5 receptor controls glutamatergic enter by means of protein kinase C-NMDA receptors in paclitaxel-induced neuropathic ache.
J Biol Chem. 2017 Dec 15;292(50):20644-20654
Authors: Xie JD, Chen SR, Pan HL
Summary
Chemotherapeutic medicine corresponding to paclitaxel trigger painful peripheral neuropathy in lots of most cancers sufferers and survivors. Though NMDA receptors (NMDARs) at main afferent terminals are recognized to be critically concerned in chemotherapy-induced power ache, the upstream signaling mechanism that results in presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a task in synaptic plasticity and NMDAR regulation. Right here we report that the Group I mGluR agonist (S)-Three,5-dihydroxyphenylglycine (DHPG) considerably elevated the frequency of miniature excitatory postsynaptic currents (EPSCs) and the amplitude of monosynaptic EPSCs evoked from the dorsal root. DHPG additionally decreased the paired-pulse ratio of evoked EPSCs in spinal dorsal horn neurons. These results had been blocked by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), however not by an mGluR1 antagonist. MPEP normalized the frequency of miniature EPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats however had no impact in vehicle-treated rats. Moreover, mGluR5 protein ranges within the dorsal root ganglion and spinal wire synaptosomes had been considerably larger in paclitaxel- than in vehicle-treated rats. Inhibiting protein kinase C (PKC) or blocking NMDARs abolished DHPG-induced will increase within the miniature EPSC frequency of spinal dorsal horn neurons in vehicle- and paclitaxel-treated rats. Furthermore, intrathecal administration of MPEP reversed ache hypersensitivity attributable to paclitaxel remedy. Our findings recommend that paclitaxel-induced painful neuropathy is related to elevated presynaptic mGluR5 exercise on the spinal wire stage, which serves as upstream signaling for PKC-mediated tonic activation of NMDARs. mGluR5 is subsequently a promising goal for lowering chemotherapy-induced neuropathic ache.
PMID: 29074619 [PubMed – indexed for MEDLINE]