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J Biol Chem. 2017 Dec 15;292(50):20644-20654. doi: 10.1074/jbc.M117.818476. Epub 2017 Oct 26.

Presynaptic mGluR5 receptor controls glutamatergic input through protein kinase C-NMDA receptors in paclitaxel-induced neuropathic pain.

Author information

1
From the Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and.
2
the Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
3
From the Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and huilinpan@mdanderson.org.

Abstract

Chemotherapeutic drugs such as paclitaxel cause painful peripheral neuropathy in many cancer patients and survivors. Although NMDA receptors (NMDARs) at primary afferent terminals are known to be critically involved in chemotherapy-induced chronic pain, the upstream signaling mechanism that leads to presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity and NMDAR regulation. Here we report that the Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the frequency of miniature excitatory postsynaptic currents (EPSCs) and the amplitude of monosynaptic EPSCs evoked from the dorsal root. DHPG also reduced the paired-pulse ratio of evoked EPSCs in spinal dorsal horn neurons. These effects were blocked by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), but not by an mGluR1 antagonist. MPEP normalized the frequency of miniature EPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats but had no effect in vehicle-treated rats. Furthermore, mGluR5 protein levels in the dorsal root ganglion and spinal cord synaptosomes were significantly higher in paclitaxel- than in vehicle-treated rats. Inhibiting protein kinase C (PKC) or blocking NMDARs abolished DHPG-induced increases in the miniature EPSC frequency of spinal dorsal horn neurons in vehicle- and paclitaxel-treated rats. Moreover, intrathecal administration of MPEP reversed pain hypersensitivity caused by paclitaxel treatment. Our findings suggest that paclitaxel-induced painful neuropathy is associated with increased presynaptic mGluR5 activity at the spinal cord level, which serves as upstream signaling for PKC-mediated tonic activation of NMDARs. mGluR5 is therefore a promising target for reducing chemotherapy-induced neuropathic pain.

KEYWORDS:

glutamate receptor; microtubule; neurophysiology; neuroscience; neurotransmitter; pain; synaptic plasticity; tubulin

PMID:
29074619
PMCID:
PMC5733599
DOI:
10.1074/jbc.M117.818476
[Indexed for MEDLINE]
Free PMC Article

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