| Reference code: | PT/FB/BL-2004-015.11 |
| Location: | Arquivo PCA - Pasta 21/2004
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Title:
| Gene therapy for pain control by manipulation of supraspinal areas: what did we learn from studies with replication defective forms of HSV-1?
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| Publication year: | 2005
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URL:
| http://www.google.pt/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=1&cad=rja&ved=0CC0QFjAA&url=http%3A%2F%2Fwww.spneurologia.com%2Findex.php%3Foption%3Dcom_docman%26task%3Ddoc_download%26gid%3D40%26Itemid%3D56&ei=kTP5UZjPCa-I7AbB_ICgBA&usg=AFQjCNErqyNXcDOGZAvhf0HogdlL1jvI3Q&sig2=8Og5nL3tGQN91cfW5RArLQ&bvm=bv.49967636,d.ZWU
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| Abstract/Results: | ABSTRACT:
Gene therapy with replication-defective forms of Herpes Simplex Virus, type 1 (HSV-1) has been used in gene therapy for nervous system diseases. In pain control field, several studies reported the benefits of peripheral applications of HSV-1 but equivalent studies were not extended to the supraspinal endogenous pain modulatory system. Since this system contains areas that strongly inhibit pain transmission at the spinal cord along with a few centers that exert pro-nociceptive effects, we reasoned that activation of antinociceptive centers combined with blockade of pronociceptive areas using gene therapy with HSV-1 as a tool may be a valuable strategy for pain relief. Before attempting this strategy, we studied the migration dynamics of HSV-1 containing the reporter gene lacZ, under control of the cytomegalovirus promoter, from the caudal ventrolateral medulla (VLM) and the dorsal reticular nucleus (DRt), respectively, antinociceptive and pronociceptive areas.
Male Wistar rats were stereotaxically injected in the VLM or DRt with a viral suspension (2x106 PFUs) of HSV-1. After 2, 4, 7, 10 or 14 days, the animals were perfused and brain sections were immunoreacted for beta-galactosidase (ß-gal), the product of lacZ expression. To characterize neurochemically the transduced neurons in the brain, double-immunodetection of ß-gal and tyrosine hydroxylase (TH) or met-enkephalin (m-ENK) was performed, the later immunocytochemical procedure using animals that received an intraventricular colchicine injection.
Neurons expressing ß-gal were numerous in some of the VLM and DRt brain afferent sources, which included pain modulatory regions. After double immunodetection of b-gal and TH, numerous transduced noradrenergic neurons from pain control areas were found to project to the DRt. The study of b-gal and m-ENK showed that transfected opioidergic neurons projecting to the DRt occurred mainly at deep cerebellar nuclei.
The present data show transgene expression upon HSV-1 injection into medullary pain centres, more widespread than expected from previous studies with that vector. Although this could represent a powerful amplification of the synaptic delivery of the transgene product, some of the putatively disadvantages of this widespread transfection may be overcome by directing transgene expression to transduced neurons of pain control areas. In the case of DRt manipulation, the use of TH-promoters in the viral construct may be a suitable strategy to restrict transduction to noradrenergic pathways while the effects of using opioid promoters should be evaluated as to collateral effects of transfecting motor control cerebellar centers.
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| Accessibility: | Document does not exist in file
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Language:
| eng
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Author:
| Martins, I.
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Secondary author(s):
| Pinto, M., Wilson, S. P., Lima, D., Tavares, I.
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Document type:
| Abstract
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Number of reproductions:
| 1
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Reference:
| Martins, I., Pinto, M., Wilson, S. P., Lima, D., & Tavares, I. (2005). Gene therapy for pain control by manipulation of supraspinal areas: what did we learn from studies with replication defective forms of HSV-1? Sinapse, 5(1), 105.
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| Indexed document: | Yes
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| Keywords: | Psychophysiology / Pain / Gene therapy
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Gene therapy for pain control by manipulation of supraspinal areas: what did we learn from studies with replication defective forms of HSV-1? |