NMDA-R1 antisense oligodeoxynucleotides modify formalin-induced nociception and spinal c-Fos expression in rat spinal cord.
Noxious peripheral stimuli (thermal, mechanical, or chemical) produce long-term adaptations in the sensitivity of central nociceptive neurons to subsequent noxious stimuli. The mechanisms responsible for this central sensitization are multifactorial, but the activation of spinal N-methyl-D-aspartate (NMDA) receptors plays a pivotal role. Using antisense oligodeoxynucleotides, we tested the role of the NR1 subunit of the NMDA receptor in the nociception and expression of the immediate early gene c-fos following formalin-induced pain. Rats received NMDA-R1 antisense, sense, or missense oligodeoxynucleotides intrathecally three times over a 48-h interval. The day after the last injection of the oligodeoxynucleotide, the formalin test was performed. Pain-related behavior was quantified by counting the incidence of flinching of the injected paw for 60 min, and the animals were perfused and the spinal cord removed for c-Fos immunohistochemistry 60 min later. Immunopositive cells were counted in the laminae I/II(0) and V of the lumbar enlargement. Treatment with NR1 antisense oligodeoxynucleotide resulted in a marked decrease in flinching. Similarly, the antisense oligodeoxynucleotide virtually abolished formalin-induced expression of c-Fos-like immunoreactivity (Fos-IR) in the spinal cord dorsal horn ipsilateral to injection. In contrast, the corresponding sense or missense oligodeoxynucleotides had no effect on either formalin-evoked behavior or c-Fos immunoreactivity. We conclude that an NR1 antisense oligodeoxynucleotide inhibits both nociceptive behavior and c-fos expression following formalin injection in rats, demonstrating that NR1 plays an important role in the development of noxious stimulation induced c-fos expression in this model.
Lee
Il-Ok
IO
Department of Anesthesiology, Korea University Guro Hospital, 80 Guro-dong, Seoul 425-020, South Korea.
Yukhananov
Rustam
R
Standaert
David G
DG
Crosby
Gregory
G
D000818:Animals; D005557:Formaldehyde; D016762:Genes, fos / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D020125:Mutation, Missense; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010146:Pain / Q000235:genetics*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism*
C409466:NR1 NMDA receptor; D020319:Oligodeoxyribonucleotides, Antisense; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde