Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury

Joachim Scholz, Daniel C. Broom, Dong Ho Youn, Charles D. Mills, Tatsuro Kohno, Marc R. Suter, Kimberly A. Moore, Isabelle Decosterd, Richard E. Coggeshall, Clifford J. Woolf

Research output: Contribution to journalArticle

302 Scopus citations

Abstract

We show that transsynaptic apoptosis is induced in the superficial dorsal horn (laminas I-III) of the spinal cord by three distinct partial peripheral nerve lesions: spared nerve injury, chronic constriction, and spinal nerve ligation. Ongoing activity in primary afferents of the injured nerve and glutamatergic transmission cause a caspase-dependent degeneration of dorsal horn neurons that is slow in onset and persists for several weeks. Four weeks after spared nerve injury, the cumulative loss of dorsal horn neurons, determined by stereological analysis, is >20%. GABAergic inhibitory interneurons are among the neurons lost, and a marked decrease in inhibitory postsynaptic currents of lamina II neurons coincides with the induction of apoptosis. Blocking apoptosis with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) prevents the loss of GABAergic interneurons and the reduction of inhibitory currents. Partial peripheral nerve injury results in pain-like behavioral changes characterized by hypersensitivity to tactile or cold stimuli. Treatment with zVAD, which has no intrinsic analgesic properties, attenuates this neuropathic pain-like syndrome. Preventing nerve injury-induced apoptosis of dorsal horn neurons by blocking caspase activity maintains inhibitory transmission in lamina II and reduces pain hypersensitivity.

Original languageEnglish (US)
Pages (from-to)7317-7323
Number of pages7
JournalJournal of Neuroscience
Volume25
Issue number32
DOIs
StatePublished - Aug 10 2005

Keywords

  • Caspase-3
  • Dorsal horn
  • GABA
  • Glutamate excitotoxicity
  • Neuropathic pain
  • Spinal inhibition

ASJC Scopus subject areas

  • Neuroscience(all)

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    Scholz, J., Broom, D. C., Youn, D. H., Mills, C. D., Kohno, T., Suter, M. R., Moore, K. A., Decosterd, I., Coggeshall, R. E., & Woolf, C. J. (2005). Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. Journal of Neuroscience, 25(32), 7317-7323. https://doi.org/10.1523/JNEUROSCI.1526-05.2005