Inhibition of carrageenan-induced spinal c-Fos activation by systemically administered c-fos antisense oligodeoxynucleotides may be facilitated by local opening of the blood-spinal cord barrier.
Proto-oncogenes of the fos and jun family are rapidly expressed in the central nervous system following various stimuli. Proto-oncogene encoded nuclear proteins such as c-Fos or c-Jun act as transcription factors that may link neuronal excitation to changes in target gene expression. However, the precise in vivo functions of proto-oncogenes in neuroplasticity are still poorly understood. In the present study the effect of systemically administered c-fos antisense oligodeoxynucleotides (ODNs) on c-Fos and dynorphin protein levels in rat L4 spinal cord has been investigated by immunohistochemistry during carrageenan-induced hindpaw inflammation. Continuous infusion of terminal-phosphorothioated c-fos antisense ODNs by subcutaneously implanted miniosmotic pumps for 3 days sequence-specifically suppressed c-Fos protein expression in dorsal horn neurons by about 50%, while the increase in c-Jun immunopositive nuclei was not affected. Digital image analysis revealed a concomitant decrease in spinal dynorphin immunoreactivity. Moreover, 48 hr after carrageenan injection into one hindpaw plasma protein extravasation was observed in numerous blood vessels in the ipsilateral dorsal horn using intravenously administered Evans Blue. Our results provide further evidence that c-Fos may contribute to the regulation of spinal dynorphin gene expression following noxious stimulation. The local increase in blood-spinal cord barrier permeability during sustained peripheral inflammation may permit penetration of hydrophilic antisense ODNs into the central nervous system.
Gillardon
F
F
II. Physiologisches Institut, Universität Heidelberg, Germany.
Vogel
J
J
Hein
S
S
Zimmermann
M
M
Uhlmann
E
E
D000818:Animals; D001483:Base Sequence; D002199:Capillary Permeability; D002351:Carrageenan / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004399:Dynorphins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos; D007249:Inflammation; D007263:Infusions, Parenteral; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides
D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D013873:Thionucleotides; D004399:Dynorphins; D002351:Carrageenan