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Molecular Pain

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Open Access 01-12-2008 | Short report

Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT₁ receptor signaling

Authors: Yan Xiao, Judith A Richter, Joyce H Hurley

Published in: Molecular Pain | Issue 1/2008

Abstract

Background

The aberrant release of the neurotransmitters, glutamate and calcitonin-gene related peptide (CGRP), from trigeminal neurons has been implicated in migraine. The voltage-gated P/Q-type calcium channel has a critical role in controlling neurotransmitter release and has been linked to Familial Hemiplegic Migraine. Therefore, we examined the importance of voltage-dependent calcium channels in controlling release of glutamate and CGRP from trigeminal ganglion neurons isolated from male and female rats and grown in culture. Serotonergic pathways are likely involved in migraine, as triptans, a class of 5-HT₁ receptor agonists, are effective in the treatment of migraine and their effectiveness may be due to inhibiting neurotransmitter release from trigeminal neurons. We also studied the effect of serotonin receptor activation on release of glutamate and CGRP from trigeminal neurons grown in culture.

Results

P/Q-, N- and L-type channels each mediate a significant fraction of potassium-stimulated release of glutamate and CGRP. We determined that 5-HT significantly inhibits potassium-stimulated release of both glutamate and CGRP. Serotonergic inhibition of both CGRP and glutamate release can be blocked by pertussis toxin and NAS-181, a 5-HT_1B/1D antagonist. Stimulated release of CGRP is unaffected by Y-25130, a 5-HT₃ antagonist and SB 200646, a 5-HT_2B/2C antagonist.

Conclusion

These data suggest that release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling in a pertussis-toxin dependent manner and probably via 5-HT₁ receptor signaling. This is the first characterization of glutamate release from trigeminal neurons grown in culture.

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Goadsby PJ, Edvinsson L, Ekman R: Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Annals of Neurology 1990, 28: 183–187. 10.1002/ana.410280213CrossRefPubMed

Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J: No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol 2005, 58: 561–568. 10.1002/ana.20605CrossRefPubMed

Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM: Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004, 350: 1104–1110. 10.1056/NEJMoa030505CrossRefPubMed

Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM: Randomized controlled trial of an oral CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology 2008, 70: 1304–1312. 10.1212/01.WNL.0000286940.29755.61CrossRefPubMed

Ferrari MD, Odink J, Bos KD, Malessy MJ, Bruyn GW: Neuroexcitatory plasma amino acids are elevated in migraine. Neurology 1990, 40: 1582–1586.CrossRefPubMed

Martinez F, Castillo J, Rodriguez JR, Leira R, Noya M: Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks. Cephalalgia 1993, 13: 89–93. 10.1046/j.1468-2982.1993.1302089.xCrossRefPubMed

Cananzi AR, D'Andrea G, Perini F, Zamberlan F, Welch KM: Platelet and plasma levels of glutamate and glutamine in migraine with and without aura. Cephalalgia 1995, 15: 132–135. 10.1046/j.1468-2982.1995.015002132.xCrossRefPubMed

Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F: LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 2004, 24: 596–602. 10.1111/j.1468-2982.2004.00723.xCrossRefPubMed

Pietrobon D, Striessnig J: Neurobiology of migraine. Nat Rev Neurosci 2003, 4: 386–398. 10.1038/nrn1102CrossRefPubMed

10.

Van Den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der KJ, Plomp JJ, Frants RR, Ferrari MD: A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004, 41: 701–710. 10.1016/S0896-6273(04)00085-6CrossRefPubMed

11.

Goadsby PJ, Edvinsson L: The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Annals of Neurology 1993, 33: 48–56. 10.1002/ana.410330109CrossRefPubMed

12.

Ma QP, Hill R, Sirinathsinghji D: Colocalization of CGRP with 5-HT1B/1D receptors and substance P in trigeminal ganglion neurons in rats. Eur J Neurosci 2001, 13: 2099–2104. 10.1046/j.0953-816x.2001.01586.xCrossRefPubMed

13.

Ma QP: Co-localization of 5-HT(1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats. Neuroreport 2001, 12: 1589–1591. 10.1097/00001756-200106130-00015CrossRefPubMed

14.

Travagli RA, Williams JT: Endogenous monoamines inhibit glutamate transmission in the spinal trigeminal nucleus of the guinea-pig. J Physiol 1996, 491 ( Pt 1): 177–185.CrossRef

15.

Jennings EA, Ryan RM, Christie MJ: Effects of sumatriptan on rat medullary dorsal horn neurons. Pain 2004, 111: 30–37. 10.1016/j.pain.2004.05.018CrossRefPubMed

16.

Teramoto T, Kuwada M, Niidome T, Sawada K, Nishizawa Y, Katayama K: A novel peptide from funnel web spider venom, omega-Aga-TK, selectively blocks, P-type calcium channels. Biochem Biophys Res Commun 1993, 196: 134–140. 10.1006/bbrc.1993.2225CrossRefPubMed

17.

McCleskey EW, Fox AP, Feldman DH, Cruz LJ, Olivera BM, Tsien RW, Yoshikami D: Omega-conotoxin: direct and persistent blockade of specific types of calcium channels in neurons but not muscle. Proc Natl Acad Sci U S A 1987, 84: 4327–4331. 10.1073/pnas.84.12.4327PubMedCentralCrossRefPubMed

18.

Hockerman GH, Peterson BZ, Johnson BD, Catterall WA: Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol 1997, 37: 361–396. 10.1146/annurev.pharmtox.37.1.361CrossRefPubMed

19.

Hurley JA, Wang M, Vasko MR: Regulation of calcium channels and CGRP release by serotonin and 5-HT1 agonists in trigeminal neurons. Society for Neuroscience 2003.

20.

Bruinvels AT, Landwehrmeyer B, Moskowitz MA, Hoyer D: Evidence for the presence of 5-HT1B receptor messenger RNA in neurons of the rat trigeminal ganglia. Eur J Pharmacol 1992, 227: 357–359. 10.1016/0922-4106(92)90017-PCrossRefPubMed

21.

Bouchelet I, Cohen Z, Case B, Seguela P, Hamel E: Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. Molecular Pharmacology 1996, 50: 219–223.PubMed

22.

Chen JJ, Vasko MR, Wu X, Staeva TP, Baez M, Zgombick, JM, Nelson DL: Multiple subtypes of serotonin receptors are expressed in rat sensory neurons in culture. J Pharmacol Exp Ther 1998, 287: 1119–1127.PubMed

23.

Wu S, Zhu M, Wang W, Wang Y, Li Y, Yew DT: Changes of the expression of 5-HT receptor subtype mRNAs in rat dorsal root ganglion by complete Freund's adjuvant-induced inflammation. Neurosci Lett 2001, 307: 183–186. 10.1016/S0304-3940(01)01946-2CrossRefPubMed

24.

Hillegaart V, Ahlenius S: Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. Br J Pharmacol 1998, 125: 1733–1743. 10.1038/sj.bjp.0702239PubMedCentralCrossRefPubMed

25.

Kennett GA, Wood MD, Glen A, Grewal S, Forbes I, Gadre A, Blackburn TP: In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol 1994, 111: 797–802.PubMedCentralCrossRefPubMed

26.

Fukuda T, Setoguchi M, Inaba K, Shoji H, Tahara T: The antiemetic profile of Y-25130, a new selective 5-HT3 receptor antagonist. Eur J Pharmacol 1991, 196: 299–305. 10.1016/0014-2999(91)90443-TCrossRefPubMed

27.

Tallaksen-Greene SJ, Young AB, Penney JB, Beitz AJ: Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Neurosci Lett 1992, 141: 79–83. 10.1016/0304-3940(92)90339-9CrossRefPubMed

28.

Storer RJ, Goadsby PJ: Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. Neuroscience 1999, 90: 1371–1376. 10.1016/S0306-4522(98)00536-3CrossRefPubMed

29.

Goadsby PJ, Classey JD: Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res 2000, 875: 119–124. 10.1016/S0006-8993(00)02630-5CrossRefPubMed

30.

Mitsikostas DD, Sanchez R, Waeber C, Moskowitz MA, Cutrer FM: The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 1998, 76: 239–248. 10.1016/S0304-3959(98)00051-7CrossRefPubMed

31.

Durham PL, Russo AF: Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. Journal of Neuroscience 1999, 19: 3423–3429.PubMed

32.

Carruthers AM, Sellers LA, Jenkins DW, Jarvie EM, Feniuk W, Humphrey PP: Adenosine A(1) receptor-mediated inhibition of protein kinase A-induced calcitonin gene-related peptide release from rat trigeminal neurons. Mol Pharmacol 2001, 59: 1533–1541.PubMed

33.

Ulrich-Lai YM, Flores CM, Harding-Rose CA, Goodis HE, Hargreaves KM: Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from rat trigeminal ganglion: evidence for intraganglionic neurotransmission. Pain 2001, 91: 219–226. 10.1016/S0304-3959(00)00439-5CrossRefPubMed

34.

Evans AR, Nicol GD, Vasko MR: Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res 1996, 712: 265–273. 10.1016/0006-8993(95)01447-0CrossRefPubMed

35.

Malmberg AB, Yaksh TL: Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 1994, 14: 4882–4890.PubMed

36.

Nebe J, Vanegas H, Neugebauer V, Schaible HG: Omega-agatoxin IVA, a P-type calcium channel antagonist, reduces nociceptive processing in spinal cord neurons with input from the inflamed but not from the normal knee joint--an electrophysiological study in the rat in vivo. Eur J Neurosci 1997, 9: 2193–2201. 10.1111/j.1460-9568.1997.tb01386.xCrossRefPubMed

37.

Durham PL, Sharma RV, Russo AF: Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. J Neurosci 1997, 17: 9545–9553.PubMed

38.

Boess FG, Martin IL: Molecular biology of 5-HT receptors. Neuropharmacology 1994, 33: 275–317. 10.1016/0028-3908(94)90059-0CrossRefPubMed

39.

Cairns BE, Sim Y, Bereiter DA, Sessle BJ, Hu JW: Influence of sex on reflex jaw muscle activity evoked from the rat temporomandibular joint. Brain Res 2002, 957: 338–344. 10.1016/S0006-8993(02)03671-5CrossRefPubMed

40.

Okamoto K, Tashiro A, Hirata H, Bereiter DA: Differential modulation of TMJ neurons in superficial laminae of trigeminal subnucleus caudalis/upper cervical cord junction region of male and cycling female rats by morphine. Pain 2005, 114: 203–211. 10.1016/j.pain.2004.12.013CrossRefPubMed

41.

Bereiter DA, Benetti AP: Amino acid release at the spinomedullary junction after inflammation of the TMJ region in male and female rats. Pain 2006, 126: 175–183. 10.1016/j.pain.2006.06.030CrossRefPubMed

42.

Holz GG, Dunlap K, Kream RM: Characterization of the electrically evoked release of substance P from dorsal root ganglion neurons: methods and dihydropyridine sensitivity. J Neurosci 1988, 8: 463–471.PubMedCentralPubMed

43.

Lipscombe D, Helton TD, Xu W: L-type calcium channels: the low down. J Neurophysiol 2004, 92: 2633–2641. 10.1152/jn.00486.2004CrossRefPubMed

44.

Huang LY, Neher E: Ca(2+)-dependent exocytosis in the somata of dorsal root ganglion neurons. Neuron 1996, 17: 135–145. 10.1016/S0896-6273(00)80287-1CrossRefPubMed

45.

Neubert JK, Maidment NT, Matsuka Y, Adelson DW, Kruger L, Spigelman I: Inflammation-induced changes in primary afferent-evoked release of substance P within trigeminal ganglia in vivo. Brain Res 2000, 871: 181–191. 10.1016/S0006-8993(00)02440-9CrossRefPubMed

46.

Devor M, Wall PD: Cross-excitation in dorsal root ganglia of nerve-injured and intact rats. J Neurophysiol 1990, 64: 1733–1746.PubMed

47.

Fields RD, Burnstock G: Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 2006, 7: 423–436. 10.1038/nrn1928PubMedCentralCrossRefPubMed

48.

Zhang X, Chen Y, Wang C, Huang LY: Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci U S A 2007, 104: 9864–9869. 10.1073/pnas.0611048104PubMedCentralCrossRefPubMed

49.

Hong KW, Kim CD, Rhim BY, Lee WS: Effect of omega-conotoxin GVIA and omega-agatoxin IVA on the capsaicin-sensitive calcitonin gene-related peptide release and autoregulatory vasodilation in rat pial arteries. J Cereb Blood Flow Metab 1999, 19: 53–60. 10.1097/00004647-199901000-00006CrossRefPubMed

50.

Asakura K, Kanemasa T, Minagawa K, Kagawa K, Yagami T, Nakajima M, Ninomiya M: alpha-eudesmol, a P/Q-type Ca(2+) channel blocker, inhibits neurogenic vasodilation and extravasation following electrical stimulation of trigeminal ganglion. Brain Res 2000, 873: 94–101. 10.1016/S0006-8993(00)02527-0CrossRefPubMed

51.

Akerman S, Williamson DJ, Goadsby PJ: Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism. Br J Pharmacol 2003, 140: 558–566. 10.1038/sj.bjp.0705456PubMedCentralCrossRefPubMed

52.

Ebersberger A, Portz S, Meissner W, Schaible HG, Richter F: Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura. Cephalalgia 2004, 24: 250–261. 10.1111/j.1468-2982.2004.00656.xCrossRefPubMed

53.

Shields KG, Storer RJ, Akerman S, Goadsby PJ: Calcium channels modulate nociceptive transmission in the trigeminal nucleus of the cat. Neuroscience 2005, 135: 203–212. 10.1016/j.neuroscience.2004.08.054CrossRefPubMed

54.

Knight YE, Bartsch T, Kaube H, Goadsby PJ: P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci 2002, 22: RC213.PubMed

55.

Moskowitz MA, Bolay H, Dalkara T: Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann Neurol 2004, 55: 276–280. 10.1002/ana.20035CrossRefPubMed

56.

Eckert SP, Taddese A, McCleskey EW: Isolation and culture of rat sensory neurons having distinct sensory modalities [published erratum appears in J Neurosci Methods 1998 Dec 31;86(1):101]. Journal of Neuroscience Methods 1997, 77: 183–190. 10.1016/S0165-0270(97)00125-8CrossRefPubMed

57.

Cahill AL, Hurley JH, Fox AP: Coexpression of cloned alpha(1B), beta(2a), and alpha(2)/delta subunits produces non-inactivating calcium currents similar to those found in bovine chromaffin cells. J Neurosci 2000, 20: 1685–1693.PubMed

58.

Vasko MR, Campbell WB, Waite KJ: Prostaglandin E2 enhances bradykinin-stimulated release of neuropeptides from rat sensory neurons in culture. J Neurosci 1994, 14: 4987–4997.PubMed

59.

Donzanti BA, Yamamoto BK: A rapid and simple HPLC microassay for biogenic amines in discrete brain regions. Pharmacol Biochem Behav 1988, 30: 795–799. 10.1016/0091-3057(88)90102-5CrossRefPubMed

60.

Gamache P, Ryan E, Svendsen C, Murayama K, Acworth IN: Simultaneous measurement of monoamines, metabolites and amino acids in brain tissue and microdialysis perfusates. J Chromatogr 1993, 614: 213–220. 10.1016/0378-4347(93)80311-QCrossRefPubMed

Title: Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling
Authors: Yan Xiao
Judith A Richter
Joyce H Hurley
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2008
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-4-12

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT₁ receptor signaling

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

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