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Molecular Pain
Published in: Molecular Pain 1/2011

Open Access 01-12-2011 | Research

Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord

Authors: Kohei Koga, Tao Chen, Xiang-Yao Li, Giannina Descalzi, Jennifer Ling, Jianguo Gu, Min Zhuo

Published in: Molecular Pain | Issue 1/2011

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Abstract

Itch sensation is one of the major sensory experiences of human and animals. Recent studies have proposed that gastrin releasing peptide (GRP) is a key neurotransmitter for itch in spinal cord. However, no direct evidence is available to indicate that GRP actually mediate responses between primary afferent fibers and dorsal horn neurons. Here we performed integrative neurobiological experiments to test this question. We found that a small population of rat dorsal horn neurons responded to GRP application with increases in calcium signaling. Whole-cell patch-clamp recordings revealed that a part of superficial dorsal horn neurons responded to GRP application with the increase of action potential firing in adult rats and mice, and these dorsal horn neurons received exclusively primary afferent C-fiber inputs. On the other hands, few Aδ inputs receiving cells were found to be GRP positive. Finally, we found that evoked sensory responses between primary afferent C fibers and GRP positive superficial dorsal horn neurons are mediated by glutamate but not GRP. CNQX, a blocker of AMPA and kainate (KA) receptors, completely inhibited evoked EPSCs, including in those Fos-GFP positive dorsal horn cells activated by itching. Our findings provide the direct evidence that glutamate is the principal excitatory transmitter between C fibers and GRP positive dorsal horn neurons. Our results will help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic disease.
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Literature
1.
2.
Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jäger T, Sandkühler J: Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006, 312: 1659–1662. 10.1126/science.1127233PubMedCrossRef
3.
Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M: The neurobiology of itch. Nat Rev Neurosci 2006, 7: 535–547. 10.1038/nrn1950PubMedCrossRef
4.
Schmelz M: Itch and pain. Neurosci Biobehav Rev 2010, 34: 171–176. 10.1016/j.neubiorev.2008.12.004PubMedCrossRef
5.
Andrew D, Craig AD: Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001, 4: 72–77. 10.1038/82924PubMedCrossRef
6.
Sun YG, Chen ZF: A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007, 448: 700–703. 10.1038/nature06029PubMedCrossRef
7.
Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF: Cellular basis of itch sensation. Science 2009, 325: 1531–1534. 10.1126/science.1174868PubMedCrossRef
8.
Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C, Hu L, Mok SI, Shah A, Savner EM, et al.: Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 2010, 65: 886–898. 10.1016/j.neuron.2010.02.025PubMedCentralPubMedCrossRef
9.
Scherrer G, Low SA, Wang X, Zhang J, Yamanaka H, Urban R, Solorzano C, Harper B, Hnasko TS, Edwards RH, Basbaum AI: VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity. Proc Natl Acad Sci USA 2010, 107: 22296–22301. 10.1073/pnas.1013413108PubMedCentralPubMedCrossRef
10.
Lagerström MC, Rogoz K, Abrahamsen B, Persson ER, Nordenankar K, Olund C, Smith C, Mendez JA, Chen ZF, Wood JN, et al.: VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 2010, 68: 529–542. 10.1016/j.neuron.2010.09.016PubMedCentralPubMedCrossRef
11.
Liu Y, Abdel Samad O, Zhang L, Duan B, Tong Q, Lopes C, Ji RR, Lowell BB, Ma Q: VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 2010, 68: 543–556. 10.1016/j.neuron.2010.09.008PubMedCentralPubMedCrossRef
12.
Tsuzuki K, Xing H, Ling J, Gu JG: Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission. J Neurosci 2004, 24: 762–771. 10.1523/JNEUROSCI.4658-03.2004PubMedCrossRef
13.
14.
Davidson S, Giesler GJ: The multiple pathways for itch and their interactions with pain. Trends Neurosci 2010, 33: 550–558. 10.1016/j.tins.2010.09.002PubMedCentralPubMedCrossRef
15.
Nakatsuka T, Park JS, Kumamoto E, Tamaki T, Yoshimura M: Plastic changes in sensory inputs to rat substantia gelatinosa neurons following peripheral inflammation. Pain 1999, 82: 39–47. 10.1016/S0304-3959(99)00037-8PubMedCrossRef
16.
Li P, Wilding TJ, Kim SJ, Calejesan AA, Huettner JE, Zhuo M: Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 1999, 397: 161–164. 10.1038/16469PubMedCrossRef
17.
Li P, Zhuo M: Substance P and neurokinin A mediate sensory synaptic transmission in young rat dorsal horn neurons. Brain Res Bull 2001, 55: 521–531. 10.1016/S0361-9230(01)00553-6PubMedCrossRef
18.
Barth AL, Gerkin RC, Dean KL: Alteration of neuronal firing properties after in vivo experience in a FosGFP transgenic mouse. J Neurosci 2004, 24: 6466–6475. 10.1523/JNEUROSCI.4737-03.2004PubMedCrossRef
19.
Clem RL, Celikel T, Barth AL: Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex. Science 2008, 319: 101–104. 10.1126/science.1143808PubMedCrossRef
20.
Nakano T, Andoh T, Lee JB, Kuraishi Y: Different dorsal horn neurons responding to histamine and allergic itch stimuli. Neuroreport 2008, 19: 723–726. 10.1097/WNR.0b013e3282fdf6c5PubMedCrossRef
21.
Nojima HSC, Cuellar JM, Carstens MI, Moore JA, Carstens E: Opioid modulation of scratching and spinal c-fos expression evoked by intradermal serotonin. J Neurosci 2003, 23: 10784–10790.PubMed
22.
Akiyama T, Merrill AW, Zanotto K, Carstens MI, Carstens E: Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice. J Pharmacol Exp Ther 2009, 329: 945–951. 10.1124/jpet.109.152256PubMedCentralPubMedCrossRef
23.
Yasaka T, Kato G, Furue H, Rashid MH, Sonohata M, Tamae A, Murata Y, Masuko S, Yoshimura M: Cell-type-specific excitatory and inhibitory circuits involving primary afferents in the substantia gelatinosa of the rat spinal dorsal horn in vitro. J Physiol 2007, 581: 603–618. 10.1113/jphysiol.2006.123919PubMedCentralPubMedCrossRef
24.
25.
Kerchner GA, Wang GD, Qiu CS, Huettner JE, Zhuo M: Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism. Neuron 2001, 32: 477–488. 10.1016/S0896-6273(01)00479-2PubMedCrossRef
26.
Levine JD, Alessandri-Haber N: TRP channels: targets for the relief of pain. Biochim Biophys Acta 2007, 1772: 989–1003.PubMedCrossRef
27.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997, 389: 816–824. 10.1038/39807PubMedCrossRef
28.
Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, Han SK: TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci USA 2009, 106: 11330–11335. 10.1073/pnas.0905605106PubMedCentralPubMedCrossRef
29.
Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, Lee CH, Kim M, Oh U: TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27: 2331–2337. 10.1523/JNEUROSCI.4643-06.2007PubMedCrossRef
30.
Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, et al.: Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 2009, 139: 1353–1365. 10.1016/j.cell.2009.11.034PubMedCentralPubMedCrossRef
31.
Sakamoto H, Kawata M: Gastrin-releasing peptide system in the spinal cord controls male sexual behaviour. J Neuroendocrinol 2009, 21: 432–435. 10.1111/j.1365-2826.2009.01847.xPubMedCrossRef
32.
Piggins HD, Goguen D, Rusak B: Gastrin-releasing peptide induces c-Fos in the hamster suprachiasmatic nucleus. Neurosci Lett 2005, 384: 205–210. 10.1016/j.neulet.2005.03.072PubMedCrossRef
33.
Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, Battey JF, Dulac C, Kandel ER, Bolshakov VY: Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 2002, 111: 905–918. 10.1016/S0092-8674(02)01116-9PubMedCrossRef
34.
Cao X, Mercaldo V, Li P, Wu LJ, Zhuo M: Facilitation of the inhibitory transmission by gastrin-releasing peptide in the anterior cingulate cortex. Mol Pain 2010, 6: 52. 10.1186/1744-8069-6-52PubMedCentralPubMedCrossRef
35.
Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, et al.: Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 2010, 330: 1400–1404. 10.1126/science.1191792PubMedCrossRef
36.
Yoshimura M, Jessell TM: Primary afferent-evoked synaptic responses and slow potential generation in rat substantia gelatinosa neurons in vitro. J Neurophysiol 1989, 62: 96–108.PubMed
37.
Yoshimura M, Jessell TM: Amino acid-mediated EPSPs at primary afferent synapses with substantia gelatinosa neurones in the rat spinal cord. J Physiol 1990, 430: 315–335.PubMedCentralPubMedCrossRef
38.
Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M: AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci 1999, 2: 972–977. 10.1038/14771PubMedCrossRef
Metadata
Title
Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord
Authors
Kohei Koga
Tao Chen
Xiang-Yao Li
Giannina Descalzi
Jennifer Ling
Jianguo Gu
Min Zhuo
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-7-47

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