Involvement of peripheral ionotropic glutamate receptors in orofacial thermal hyperalgesia in rats

<p>Abstract</p> <p>Background</p> <p>The purpose of the present study was to elucidate the mechanisms that may underlie the sensitization of trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) neurons to heat or cold stimulation of the orofacial region following glutamate (Glu) injection.</p> <p>Results</p> <p>Glu application to the tongue or whisker pad skin caused an enhancement of head-withdrawal reflex and extracellular signal-regulated kinase (ERK) phosphorylation in Vc-C2 neurons. Head-withdrawal reflex and ERK phosphorylation were also enhanced following cold stimulation of the tongue but not whisker pad skin in Glu-injected rats, and the head-withdrawal reflex and ERK phosphorylation were enhanced following heat stimulation of the tongue or whisker pad skin. The enhanced head-withdrawal reflex and ERK phosphorylation after heat stimulation of the tongue or whisker pad skin, and those following cold stimulation of the tongue but not whisker pad skin were suppressed following ionotropic glutamate receptor antagonists administration into the tongue or whisker pad skin. Furthermore, intrathecal administration of MEK1/2 inhibitor PD98059 caused significant suppression of enhanced head-withdrawal reflex in Glu-injected rats, heat head-withdrawal reflex in the rats with Glu injection into the tongue or whisker pad skin and cold head-withdrawal reflex in the rats with Glu injection into the tongue.</p> <p>Conclusions</p> <p>The present findings suggest that peripheral Glu receptor mechanisms may contribute to cold hyperalgesia in the tongue but not in the facial skin, and also contribute to heat hyperalgesia in the tongue and facial skin, and that the mitogen-activated protein kinase cascade in Vc-C2 neurons may be involved in these Glu-evoked hyperalgesic effects.</p

TRIC-A Channels in Vascular Smooth Muscle Contribute to Blood Pressure Maintenance.

小胞体カウンターイオンチャネルTRICチャネルによる血圧調節機構とTRICチャネル遺伝子多型による本態性高血圧リスク. 京都大学プレスリリース. 2011-08-02.TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation channels postulated to mediate counter-ion movements facilitating physiological Ca(2+) release from internal stores. Tric-a-knockout mice developed hypertension during the daytime due to enhanced myogenic tone in resistance arteries. There are two Ca(2+) release mechanisms in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca(2+) sparks to induce hyperpolarization, while agonist-induced activation of inositol trisphosphate receptors (IP(3)Rs) evokes global Ca(2+) transients causing contraction. Tric-a gene ablation inhibited RyR-mediated hyperpolarization signaling to stimulate voltage-dependent Ca(2+) influx, and adversely enhanced IP(3)R-mediated Ca(2+) transients by overloading Ca(2+) stores in VSMCs. Moreover, association analysis identified single-nucleotide polymorphisms (SNPs) around the human TRIC-A gene that increase hypertension risk and restrict the efficiency of antihypertensive drugs. Therefore, TRIC-A channels contribute to maintaining blood pressure, while TRIC-A SNPs could provide biomarkers for constitutional diagnosis and personalized medical treatment of essential hypertension

Involvement of AMPA Receptor GluR2 and GluR3 Trafficking in Trigeminal Spinal Subnucleus Caudalis and C1/C2 Neurons in Acute-Facial Inflammatory Pain

<div><p>To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI), GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR) cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16–60 min following formalin injection, resulting in orofacial inflammatory pain.</p> </div

Expression of pERK-IR cells in Vi/Vc, Vc and C1/C2 after formalin injection.

<p>A: High magnification photomicrographs of pERK-IR cells (Aa), NeuN positive cells (Ab) and NeuN-labeled pERK-IR cells (Ac) at 5 min after formalin injection in the Vc of wild-type mice. B, C and D: low magnification photomicrographs of pERK-IR cells in the dorsal (B), middle (C) and ventral (D) portions of the Vc 5 min after formalin injection in wild-type mice. E: Camera lucida drawings of pERK-IR cells in the wild-type mice at 5 min after subcutaneous formalin injection into the whisker pad skin in sections from −1440 µm to the obex. F and G: Rostro-caudal distribution of pERK-IR cells in the wild-type, GluR2 delta7 KI and GluR3 delta7 KI mice 40 min after formalin injection in the ipsilateral and contralateral whisker pads, respectively. The mean number of pERK-IR cells in the ipsilateral (H) and contralateral (I) Vi/Vc, Vc and C1/C2 in the wild-type, GluR2 delta7 KI and GluR3 delta7 KI mice 40 min after subcutaneous formalin injection into the whisker pad skin. Boxes in the 3^rd panel in E indicate areas in B, C and D. Five min data are presented besides the 40 min ones in H and I.</p