Dynamic of migration of HSV-1 from a medullary pronociceptive centre: antinociception by overexpression of the preproenkephalin transgene.
Herpes Simplex Virus type 1 (HSV-1) vectors are known to inhibit nociceptive transmission at the spinal cord after peripheral applications. Similar approaches may also be useful when applied at the supraspinal pain control system as the system includes pronociceptive (facilitatory) components. We performed a study aimed to analyse the migration of HSV-1 along with the inhibition of pronociception from the medullary dorsal reticular nucleus (DRt), a major facilitatory component of the supraspinal pain control system. To study the migration, a HSV-1 vector expressing lacZ under control of the human cytomegalovirus (hCMV) promoter was injected in the DRt and the expression of beta-galactosidase (beta-gal) was detected at 2, 4, 7, 10 and 14 days. Numerous beta-gal-immunoreactive neurons were observed at the injection site until day 4, and at some of the brain areas projecting to the DRt until day 7. To block the pronociceptive effects of the DRt, a HSV-1 vector expressing the preproenkephalin transgene, under the control of hCMV promoter, was injected into the DRt. Behavioural evaluation was performed at the time-points referred above, using the paw withdrawal latency test to evaluate thermal nociceptive responses. Anti-hyperalgesic effects persisted during 4 days, decreasing after that time-point. The present study demonstrates that selective migration of HSV-1 should be considered in gene therapy strategies based on HSV-1 injections into the brain. The study also shows that it is possible to decrease pain facilitation from the brain using opioidergic inhibition of pronociceptive supraspinal areas.
Martins
I
I
Instituto de Histologia & Embriologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
Pinto
M
M
Wilson
S P
SP
Lima
D
D
Tavares
I
I
D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics; D004745:Enkephalins / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000378:metabolism*; D009434:Neural Pathways / Q000166:cytology / Q000378:metabolism; D009619:Nociceptors / Q000166:cytology / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D059408:Pain Management; D010147:Pain Measurement; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D011930:Reaction Time / Q000235:genetics; D012154:Reticular Formation / Q000166:cytology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D016896:Treatment Outcome
D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin