Reference code: | PT/FB/BL-2004-015.09 |
Location: | Arquivo PCA - Pasta 21/2004
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Title:
| Gene therapy for chronic pain control: Perspectives of HSV-1 mediated gene transfer to supraspinal centres
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Publication year: | 2005
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URL:
| http://www.nature.com/mt/journal/v11/n1s/abs/mt2005278a.html
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Abstract/Results: | ABSTRACT:
Subcutaneous application of Herpes Simplex Virus type 1 (HSV-1) vectors mediating enkephalin transfer to the sensory neurons of the dorsal root ganglia, were shown to induce analgesia and reduce hyperalgesic reactions. These results prompted to use these vectors in the treatment of chronic intractable pain and human clinical trials based on these approaches are expected in the near future. Since brainstem regions are major pain control centres, HSV-1 mediating gene transfer at supraspinal level could also represent a major breakthrough for pain relief. Taking this into consideration, our purpose is the activation of antinociceptive supraspinal centers and blockade of pronociceptive areas. Before attempting this, we studied the migration dynamics of a replication-defective HSV-1 vector 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 of HSV-1 (2|[times]|106 PFUs). At 2, 4, 7, 10 and 14 days post-injection, brain sections were immunoreacted for beta-galactosidase (b-gal). To charaterize neurochemically transduced neurons, double-immunodetection of b-gal and tyrosine hydroxylase (TH) or met-enkephalin (m-ENK), the later immunocytochemical procedure using animals that received intraventricular colchicine injections, prior to sacrifice.
Neurons expressing b-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 were observed after DRt injections in several pain control areas such as the locus coeruleus and the A5 cell group. The study of b-gal and m-ENK showed that transduced opioidergic neurons projecting to the DRt occurred mainly at deep cerebellar nuclei while those projecting to the VLM occurred at the medullar gigantocellular nucleus, an important pain control area.
These data indicate that restricting transgene expression in the brain is a suitable strategy to selectively target nociceptive pathways controlling the activity of the VLM and DRt namely by including tissue specific promoters in this viral construct. For the DRt, a TH promoter may allow to restrict transgene expression to noradrenergic pain control areas. Similarly, in the case of the VLM, a pre-proenkephalin promoter may be useful to restrict transgene expression to the gigantocellular nucleus. However, restricting opioidergic expression to deep cerebellar nuclei for pain control to modulate DRt activity, should include parallel evaluation of collateral motor effects.
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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., Pereira, S., 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., Pereira, S., Wilson, S. P., Lima, D., & Tavares, I. (2005). Gene therapy for chronic pain control: Perspectives of HSV-1 mediated gene transfer to supraspinal centres. Molecular Therapy, 11(Supplement 1), S63-S64. doi: 10.1016/j.ymthe.2005.06.162
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Indexed document: | Yes
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Keywords: | Psychophysiology / Pain
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Gene therapy for chronic pain control: Perspectives of HSV-1 mediated gene transfer to supraspinal centres |