Antihyperalgesic effect of a recombinant herpes virus encoding antisense for calcitonin gene-related peptide.
BACKGROUND
Calcitonin gene-related peptide (CGRP) is contained in and released by small-diameter, nociceptive primary afferent sensory neurons. Upon spinal release, one of the effects of CGRP seems to be to sensitize dorsal horn neurons to subsequent input from nociceptive afferents and, consequently, to induce a behavioral hyperalgesia. Therefore, attenuating evoked release of CGRP from central terminals of nociceptors should have an antihyperalgesic effect.


METHODS
The authors applied a recombinant herpes vector, encoding an antisense sequence to the whole CGRP gene, to the dorsal surface of the hind paw of mice to knock down expression of the peptide selectively in primary afferents innervating this tissue.


RESULTS
Herpes virus-based vector encoding an antisense sequence for the whole CGRP clearly reduced CGRP immunoreactivity in the infected spinal dorsal horn levels as well as in cultured dorsal root ganglia neurons. Selective knockdown of CGRP in primary afferents significantly attenuated the thermal, C-fiber hyperalgesia normally observed after topical application of capsaicin. The effect of viral vector-mediated knockdown of CGRP was comparable to the effect of intrathecal application of the CGRP antagonist CGRP8-37, but lasted for 14 weeks after one single application.


CONCLUSIONS
Viral vector-mediated knockdown of CGRP in primary afferent neurons provides a promising tool for treatment of chronic pain states as well as for studies investigating the pathophysiology underlying these conditions.
Tzabazis
Alexander Z
AZ
Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA. tzabazis@web.de
Pirc
Geanine
G
Votta-Velis
Effrossyni
E
Wilson
Steven P
SP
Laurito
Charles E
CE
Yeomans
David C
DC
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D006930:Hyperalgesia; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D059408:Pain Management; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D015740:Calcitonin Gene-Related Peptide