Neurotrophin-3 antisense oligonucleotide attenuates nerve injury-induced Abeta-fibre sprouting.
It is proposed that following peripheral nerve injury abnormal sprouting of Abeta-fibre primary afferent neurons in the spinal cord contributes to the allodynia that often occurs with such injury. Allodynia is characterized as pain due to a stimulus which is normally non-noxious. Our recent in vivo experiments show that intrathecal administration of neurotrophin-3 (NT-3), in normal animals, induces allodynia and sprouting of Abeta-fibres. In this study, we examine whether intrathecal administration of NT-3 antisense oligonucleotides (50 microM), via an osmotic pump for 14 days, attenuates nerve injury-induced sprouting and allodynia. The oligonucleotides used in this study were phosphorothioate modified and control experiments, using an ELISA, confirm that intrathecal administration of the antisense induces a significant decrease in NT-3 levels in the spinal cord. All surgery was conducted on anaesthetized Wistar rats (sodium pentobarbitone, i.p. 50 mg/kg). Consistent with previous studies, transganglionic labelling of Abeta-fibres with choleragenoid-horseradish peroxidase (C-HRP) shows that complete transection of the sciatic nerve induces an expansion of C-HRP label into lamina II of the spinal dorsal horn. Using image analysis, we find that intrathecal administration of NT-3 antisense attenuates the density of C-HRP labelling in lamina II in nerve injured animals. A NT-3 sense oligonucleotide (50 microM) has no effect. To test the effect of NT-3 antisense on allodynia, the nociceptive flexion reflex is examined, using an Ugo Basile Analgesymeter, in animals with partial sciatic nerve ligation. Intrathecal administration of 50 microM NT-3 antisense significantly attenuates nerve injury-induced allodynia, whereas the sense oligonucleotide has no effect. These results provide further evidence that endogenous NT-3 contributes to both nerve injury-induced Abeta-fibre sprouting and allodynia and demonstrates the potential of neurotrophin-3 antisense oligonucleotides as therapeutic agents for neuropathic pain.
White
D M
DM
Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, N.S.W. 2065, St. Leonards, Australia. debbeau@ozemail.com.au
D000818:Animals; D006735:Horseradish Peroxidase; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D020933:Neurotrophin 3 / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D012585:Sciatica / Q000503:physiopathology / Q000628:therapy
D020933:Neurotrophin 3; D016376:Oligonucleotides, Antisense; D006735:Horseradish Peroxidase