Involvement of GluR2 and GluR3 subunit C-termini in the trigeminal spinal subnucleus caudalis and C1–C2 neurons in trigeminal neuropathic pain

doi:10.1016/j.neulet.2010.12.060

Neuroscience Letters

Volume 491, Issue 1, 10 March 2011, Pages 8-12

https://doi.org/10.1016/j.neulet.2010.12.060 Get rights and content

Abstract

To clarify the involvement of GluR2 and GluR3 subunits of AMPA receptor in orofacial neuropathic pain, we studied changes in nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation followed by infraorbital nerve (ION)-partial transection model applied to GluR2 or GluR3 delta7 knock-in (KI) mice. In these animals, last seven amino acids of GluR2 or GluR3 subunit, the binding sites of interacting protein, are deleted in vivo. Head-withdrawal threshold to mechanical stimulation of the whisker pad skin ipsilateral to ION-partial transection was significantly reduced at 1, 3, 5, 7, 11 and 14 days after transection compared with that before transection in wild-type mice. In the GluR2 and GluR3 delta7 KI mice, the head-withdrawal threshold did not change following ION-partial transection. The number of pERK-LI cells examined in Vc and C1–C2 in wild-type mice after the non-noxious stimulation was larger than that of GluR2 and GluR3 delta7 KI mice.

The present findings suggest that GluR2 and GluR3 subunits of AMPA receptor play roles in the trigeminal nerve injury-mediated enhancement of Vc and C1–C2 neuronal excitability, and hyperalgesia.

Research highlights

▶ ION-partial transection was performed in the GluR2 and GluR3 delta7 KI mice. ▶ Mechanical allodynia in the face was depressed. ▶ ERK phosphorylation in Vc neurons was depressed. ▶ Membrane trafficking of GluR2 and GluR3 subunits is involved in orofacial neuropathic pain.

Section snippets

Acknowledgments

This study was supported in part by Research Grants from Sato and Uemura Funds from Nihon University School of Dentistry, and a grant from the Dental Research Center, Nihon University School of Dentistry; Nihon University multidisciplinary research grant for KI; grants from the Ministry of Education, Culture, Sports, Science, and Technology to promote multidisciplinary research project “Translational Research Network on Orofacial Neurological Disorders” at Nihon University School of Dentistry;

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It was widely accepted that central sensitization was a important diver of neuropathic pain. AMPA receptors were a kind of ionotropic glutamate receptors involved in excitatory neurotransmission and spinal central sensitization in neuropathic pain (Miletic et al., 2015; Miyamoto et al., 2011). However, AMPARs were important for neuronal development and brain functions (such as memory)(Hamad et al., 2011; Malenka, 2003).
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ION-CCI causes a marked increase in neuronal excitability and gene expression in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) neurons, as well as in trigeminal ganglion (TG) neurons [10,24]. Some recent studies reported that MAPK pathways in Vc and C1-C2 neurons were important in the development of orofacial neuropathic pain in a rat model of trigeminal nerve injury [12,19]. ION-CCI, inferior alveolar nerve transection, and upper cervical spinal nerve transection were reported to enhance phosphorylation of extracellular signal-regulated kinase (ERK) in Vc and C1-C2 neurons [15,22,25].
We investigated the effect of botulinum neurotoxin type A (BoNT-A) on mechanical allodynia and hyperalgesia associated with infraorbital nerve constriction (ION-CCI) in rats. ION-CCI rats received a subcutaneous BoNT-A injection into the whisker pad area on day 7 postoperatively and underwent pain assessment on days 14 and 21 postoperatively. Rats were assigned to one of four treatment groups (n = 5 each): ION-CCI + BoNT-A 20 pg (low-dose group), ION-CCI + BoNT-A 200 pg (high-dose group), ION-CCI + saline, and Sham. Mechanical allodynia and hyperalgesia were evaluated preoperatively (baseline) and on days 7, 14, and 21 postoperatively. After noxious mechanical stimulation of whisker pad skin, the number and distribution pattern of the phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons were analyzed in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). On day 21, nocifensive behavior was attenuated by high-dose but not low-dose BoNT-A administration. In addition, after noxious mechanical stimulation of whisker pad skin, the numbers of pERK-IR cells in the superficial laminae of Vc and C1-C2 were significantly lower in the high-dose BoNT-A group than in the ION-CCI + saline group. The present findings suggest that, by suppressing Vc neuronal activity, high-dose intradermal injection of BoNT-A at the site of ION innervation alleviates mechanical facial allodynia and hyperalgesia associated with ION-CCI.
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Iwata et al have reported that the mechanical thresholds in the ipsilateral vibrissal pad area are significantly lower than those of sham-operated rats for 4 weeks following inferior alveolar nerve transection, and that the contralateral side also shows transient decreases in mechanical thresholds.23,24,36 In a mouse p-IONX model, mechanical allodynia is also observed bilaterally.31 The p-IONX rats in the present study also showed mechanical allodynia reflected on both sides of the face as a lowered mechanical withdrawal threshold that began at postoperative day 1, peaked at postoperative days 5 to 10, were maintained to day 28, and returned to baseline levels by postoperative day 35.
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Involvement of GluR2 and GluR3 subunit C-termini in the trigeminal spinal subnucleus caudalis and C1–C2 neurons in trigeminal neuropathic pain

Abstract

Research highlights

Section snippets

Acknowledgments

Neuropharmacology

Neuron

Neuron

Brain Res.

Neuron

Neuron

Neuron

Neuron

Neuron

Cell

Neuron

Neuron

Neuron

Neuron

Brain Res.

Pain

The glutamate receptor ion channels

Pharmacol. Rev.

GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors

Nature

The distribution of neurons expressing calcium-permeable AMPA receptors in the superficial laminae of the spinal cord dorsal horn

J. Neurosci.