Top

Published in:

Open Access 01-12-2009 | Research

Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia

Authors: Jean-Philippe Vit, Peter T Ohara, Christopher Sundberg, Blanca Rubi, Pierre Maechler, Chunyan Liu, Mariana Puntel, Pedro Lowenstein, Maria Castro, Luc Jasmin

Published in: Molecular Pain | Issue 1/2009

Abstract

Background

Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion.

Results

Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist.

Conclusion

Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya.

Available only for authorised users

Coderre TJ, Katz J, Vaccarino AL, Melzack R: Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993, 52: 259–285. 10.1016/0304-3959(93)90161-HPubMedCrossRef

Coderre TJ, Vaccarino AL, Melzack R: Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res 1990, 535: 155–158. 10.1016/0006-8993(90)91835-5PubMedCrossRef

Naik AK, Pathirathna S, Jevtovic-Todorovic V: GABA(A) receptor modulation in dorsal root ganglia in vivo affects chronic pain after nerve injury. Neuroscience 2008, 154: 1539–1553. 10.1016/j.neuroscience.2008.04.061PubMedCrossRef

Hayasaki H, Sohma Y, Kanbara K, Maemura K, Kubota T, Watanabe M: A local GABAergic system within rat trigeminal ganglion cells. Eur J Neurosci 2006, 23: 745–757. 10.1111/j.1460-9568.2006.04602.xPubMedCrossRef

Jasmin L, Wu MV, Ohara PT: GABA puts a stop to pain. Curr Drug Targets CNS Neurol Disord 2004, 3: 487–505. 10.2174/1568007043336716PubMedCrossRef

Liu J, Wolfe D, Hao S, Huang S, Glorioso JC, Mata M, Fink DJ: Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain. Mol Ther 2004, 10: 57–66. 10.1016/j.ymthe.2004.04.017PubMedCrossRef

Lee JY, Fink DJ, Mata M: Vector-mediated gene transfer to express inhibitory neurotransmitters in dorsal root ganglion reduces pain in a rodent model of lumbar radiculopathy. Spine 2006, 31: 1555–1558. 10.1097/01.brs.0000222060.88919.58PubMedCrossRef

Liu W, Liu Z, Liu L, Xiao Z, Cao X, Cao Z, Xue L, Miao L, He X, Li W: A novel human foamy virus mediated gene transfer of GAD67 reduces neuropathic pain following spinal cord injury. Neurosci Lett 2008, 432: 13–18.PubMedCrossRef

Smith-Arica JR, Morelli AE, Larregina AT, Smith J, Lowenstein PR, Castro MG: Cell-type-specific and regulatable transgenesis in the adult brain: adenovirus-encoded combined transcriptional targeting and inducible transgene expression. Mol Ther 2000, 2: 579–587. 10.1006/mthe.2000.0215PubMedCrossRef

10.

Baker AH: Adenovirus toxicity and tropism in vivo: not as simple as A, B, C (or D, E, F). Mol Ther 2007, 15: 2061–2062. 10.1038/sj.mt.6300349PubMedCrossRef

11.

Rubio N, Martin-Clemente B: Binding of adenovirus to its receptors in mouse astrocytes induces c-fos proto-oncogene and apoptosis. Virology 2002, 297: 211–219. 10.1006/viro.2002.1426PubMedCrossRef

12.

Santis G, Legrand V, Hong SS, Davison E, Kirby I, Imler JL, Finberg RW, Bergelson JM, Mehtali M, Boulanger P: Molecular determinants of adenovirus serotype 5 fibre binding to its cellular receptor CAR. J Gen Virol 1999,80(Pt 6):1519–1527.PubMed

13.

Meunier A, Pohl M: Lentiviral vectors for gene transfer into the spinal cord glial cells. Gene Ther 2009, 16: 476–482. 10.1038/gt.2009.22PubMedCrossRef

14.

Clavelou P, Dallel R, Orliaguet T, Woda A, Raboisson P: The orofacial formalin test in rats: effects of different formalin concentrations. Pain 1995, 62: 295–301. 10.1016/0304-3959(94)00273-HPubMedCrossRef

15.

Allen AM, Dosanjh JK, Erac M, Dassanayake S, Hannan RD, Thomas WG: Expression of constitutively active angiotensin receptors in the rostral ventrolateral medulla increases blood pressure. Hypertension 2006, 47: 1054–1061. 10.1161/01.HYP.0000218576.36574.54PubMedCrossRef

16.

Oh S, Pluhar GE, McNeil EA, Kroeger KM, Liu C, Castro MG, Lowenstein PR, Freese A, Ohlfest JR: Efficacy of nonviral gene transfer in the canine brain. J Neurosurg 2007, 107: 136–144. 10.3171/JNS-07/07/0136PubMedCentralPubMedCrossRef

17.

Hou ST, Jiang SX, Huang D, Desbois A: A novel adenoviral vector-mediated neuronal selective gene expression in neonatal mouse brain in response to hypoxia. Neurosci Lett 2007, 419: 23–27. 10.1016/j.neulet.2007.03.059PubMedCrossRef

18.

Chen J, Wu J, Apostolova I, Skup M, Irintchev A, Kugler S, Schachner M: Adeno-associated virus-mediated L1 expression promotes functional recovery after spinal cord injury. Brain 2007, 130: 954–969. 10.1093/brain/awm049PubMedCrossRef

19.

Watkins LR, Hutchinson MR, Milligan ED, Maier SF: "Listening" and "talking" to neurons: implications of immune activation for pain control and increasing the efficacy of opioids. Brain Res Rev 2007, 56: 148–169. 10.1016/j.brainresrev.2007.06.006PubMedCentralPubMedCrossRef

20.

Carnevale D, De Simone R, Minghetti L: Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets 2007, 6: 388–397. 10.2174/187152707783399193PubMedCrossRef

21.

Fields RD, Burnstock G: Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 2006, 7: 423–436. 10.1038/nrn1928PubMedCentralPubMedCrossRef

22.

Hanani M: Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev 2005, 48: 457–476. 10.1016/j.brainresrev.2004.09.001PubMedCrossRef

23.

Vit JP, Jasmin L, Bhargava A, Ohara PT: Satellite glial cells in the trigeminal ganglion as a determinant of orofacial neuropathic pain. Neuron Glia Biol 2006, 2: 247–257. 10.1017/S1740925X07000427PubMedCentralPubMedCrossRef

24.

Danbolt NC: Glutamate uptake. Prog Neurobiol 2001, 65: 1–105. 10.1016/S0301-0082(00)00067-8PubMedCrossRef

25.

Liu W, Liu Z, Cao X, Cao Z, Xue L, Zhu F, He X, Li W: Recombinant human foamy virus, a novel vector for neurological disorders gene therapy, drives production of GAD in cultured astrocytes. Mol Ther 2007, 15: 1834–1841. 10.1038/sj.mt.6300224PubMedCrossRef

26.

New KC, Rabkin SD: GABA synthesis in astrocytes after infection with defective herpes simplex virus vectors expressing glutamic acid decarboxylase 65 or 67. J Neurochem 1998, 71: 2304–2312.PubMedCrossRef

27.

Sacchettoni SA, Benchaibi M, Sindou M, Belin MF, Jacquemont B: Glutamate-modulated production of GABA in immortalized astrocytes transduced by a glutamic acid decarboxylase-expressing retrovirus. Glia 1998, 22: 86–93. 10.1002/(SICI)1098-1136(199801)22:1<86::AID-GLIA8>3.0.CO;2-6PubMedCrossRef

28.

Minchin MC: Factors influencing the efflux of [3H]gamma-aminobutyric acid from satellite glial cells in rat sensory ganglia. J Neurochem 1975, 24: 571–577. 10.1111/j.1471-4159.1975.tb07676.xPubMedCrossRef

29.

Minchin MC, Iversen LL: Release of (3H)gamma-aminobutyric acid from glial cells in rat dorsal root ganglia. J Neurochem 1974, 23: 533–540. 10.1111/j.1471-4159.1974.tb06056.xPubMedCrossRef

30.

Roberts PJ: Amino acid release from isolated rat dorsal root ganglia. Brain Res 1974, 74: 327–332. 10.1016/0006-8993(74)90586-1PubMedCrossRef

31.

Magnaghi V: GABA and Neuroactive Steroid Interactions in Glia: New Roles for Old Players? Curr Neuropharmacol 2007, 5: 47–64. 10.2174/157015907780077132PubMedCentralPubMedCrossRef

32.

Labrakakis C, Tong CK, Weissman T, Torsney C, MacDermott AB: Localization and function of ATP and GABA A receptors expressed by nociceptors and other postnatal sensory neurons in rat. J Physiol 2003, 549: 131–142. 10.1113/jphysiol.2002.031963PubMedCentralPubMedCrossRef

33.

Toulme E, Blais D, Leger C, Landry M, Garret M, Seguela P, Boue-Grabot E: An intracellular motif of P2X(3) receptors is required for functional cross-talk with GABA(A) receptors in nociceptive DRG neurons. J Neurochem 2007, 102: 1357–1368. 10.1111/j.1471-4159.2007.04640.xPubMedCrossRef

34.

Desarmenien M, Feltz P, Occhipinti G, Santangelo F, Schlichter R: Coexistence of GABA A and GABA B receptors on A delta and C primary afferents. Br J Pharmacol 1984, 81: 327–333.PubMedCentralPubMedCrossRef

35.

Si JQ, Li ZW, Hu HZ, Zhou XP, Guan BC: Inhibitory effect of baclofen on GABA-induced depolarization and GABA-activated current in primary sensory neurons. Neuroscience 1997, 81: 821–827. 10.1016/S0306-4522(97)00107-3PubMedCrossRef

36.

Nakagawa H, Hiura A, Kubo Y: Preliminary studies on GABA-immunoreactive neurons in the rat trigeminal ganglion. Okajimas Folia Anat Jpn 2003, 80: 15–21. 10.2535/ofaj.80.15PubMedCrossRef

37.

Szabat E, Soinila S, Happola O, Linnala A, Virtanen I: A new monoclonal antibody against the GABA-protein conjugate shows immunoreactivity in sensory neurons of the rat. Neuroscience 1992, 47: 409–420. 10.1016/0306-4522(92)90255-ZPubMedCrossRef

38.

Liu J, Tai C, de Groat WC, Peng XM, Mata M, Fink DJ: Release of GABA from sensory neurons transduced with a GAD67-expressing vector occurs by non-vesicular mechanisms. Brain Res 2006, 1073–1074: 297–304. 10.1016/j.brainres.2005.12.091PubMedCrossRef

39.

Todd AJ: Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor. Exp Physiol 2002, 87: 245–249. 10.1113/eph8702351PubMedCrossRef

40.

Todd AJ, Watt C, Spike RC, Sieghart W: Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord. J Neurosci 1996, 16: 974–982.PubMed

41.

Valtschanoff JG, Weinberg RJ, Rustioni A: Amino acid immunoreactivity in corticospinal terminals. Exp Brain Res 1993, 93: 95–103. 10.1007/BF00227784PubMedCrossRef

42.

Hao S, Mata M, Wolfe D, Huang S, Glorioso JC, Fink DJ: Gene transfer of glutamic acid decarboxylase reduces neuropathic pain. Ann Neurol 2005, 57: 914–918. 10.1002/ana.20483PubMedCentralPubMedCrossRef

43.

Coderre TJ, Melzack R: The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci 1992, 12: 3665–3670.PubMed

44.

Bao L, Jin SX, Zhang C, Wang LH, Xu ZZ, Zhang FX, Wang LC, Ning FS, Cai HJ, Guan JS, et al.: Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 2003, 37: 121–133. 10.1016/S0896-6273(02)01103-0PubMedCrossRef

45.

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)80287-1PubMedCrossRef

46.

Ouyang K, Zheng H, Qin X, Zhang C, Yang D, Wang X, Wu C, Zhou Z, Cheng H: Ca2+ sparks and secretion in dorsal root ganglion neurons. Proc Natl Acad Sci USA 2005, 102: 12259–12264. 10.1073/pnas.0408494102PubMedCentralPubMedCrossRef

47.

Zhang C, Xiong W, Zheng H, Wang L, Lu B, Zhou Z: Calcium- and dynamin-independent endocytosis in dorsal root ganglion neurons. Neuron 2004, 42: 225–236. 10.1016/S0896-6273(04)00189-8PubMedCrossRef

48.

Zhang C, Zhou Z: Ca(2+)-independent but voltage-dependent secretion in mammalian dorsal root ganglion neurons. Nat Neurosci 2002, 5: 425–430.PubMed

49.

Zhang X, Aman K, Hokfelt T: Secretory pathways of neuropeptides in rat lumbar dorsal root ganglion neurons and effects of peripheral axotomy. J Comp Neurol 1995, 352: 481–500. 10.1002/cne.903520402PubMedCrossRef

50.

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 USA 2007, 104: 9864–9869. 10.1073/pnas.0611048104PubMedCentralPubMedCrossRef

51.

Takeda M, Tanimoto T, Nasu M, Ikeda M, Kadoi J, Matsumoto S: Activation of NK1 receptor of trigeminal root ganglion via substance P paracrine mechanism contributes to the mechanical allodynia in the temporomandibular joint inflammation in rats. Pain 2005, 116: 375–385. 10.1016/j.pain.2005.05.007PubMedCrossRef

52.

Rubi B, Ishihara H, Hegardt FG, Wollheim CB, Maechler P: GAD65-mediated glutamate decarboxylation reduces glucose-stimulated insulin secretion in pancreatic beta cells. J Biol Chem 2001, 276: 36391–36396. 10.1074/jbc.M104999200PubMedCrossRef

53.

Hurtado-Lorenzo A, David A, Thomas C, Castro MG, Lowenstein PR: Use of Recombinant Adenovirus for Gene Transfer into the Rat Brain: Evaluation of Gene Transfer Efficiency, Toxicity, and Inflammatory and Immune Reactions. Methods in Molecular Medicine 2002, 76: 113–133.

54.

Raboisson P, Dallel R: The orofacial formalin test. Neurosci Biobehav Rev 2004, 28: 219–226. 10.1016/j.neubiorev.2003.12.003PubMedCrossRef

55.

Vit JP, Ohara PT, Bhargava A, Kelley K, Jasmin L: Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury. J Neurosci 2008, 28: 4161–4171. 10.1523/JNEUROSCI.5053-07.2008PubMedCentralPubMedCrossRef

56.

Margeta-Mitrovic M, Mitrovic I, Riley RC, Jan LY, Basbaum AI: Immunohistochemical localization of GABA(B) receptors in the rat central nervous system. J Comp Neurol 1999, 405: 299–321. 10.1002/(SICI)1096-9861(19990315)405:3<299::AID-CNE2>3.0.CO;2-6PubMedCrossRef

Title: Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia
Authors: Jean-Philippe Vit
Peter T Ohara
Christopher Sundberg
Blanca Rubi
Pierre Maechler
Chunyan Liu
Mariana Puntel
Pedro Lowenstein
Maria Castro
Luc Jasmin
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2009
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-5-42

At a glance: The STEP trials

Springer Medicine

Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia

Abstract

Background

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2009

Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity

Involvement of S-nitrosylation of actin in inhibition of neurotransmitter release by nitric oxide

Reactive oxygen species mediate TNFR1 increase after TRPV1 activation in mouse DRG neurons

NF-κB mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons

Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex

Lysophosphatidic acid-3 receptor-mediated feed-forward production of lysophosphatidic acid: an initiator of nerve injury-induced neuropathic pain