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The Journal of Neuroscience, August 10, 2005, 25(32):7317-7323; doi:10.1523/JNEUROSCI.1526-05.2005

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Behavioral/Systems/Cognitive
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,¹ Daniel C. Broom,¹ Dong-Ho Youn,¹ Charles D. Mills,¹ Tatsuro Kohno,¹ Marc R. Suter,² Kimberly A. Moore,¹ Isabelle Decosterd,² Richard E. Coggeshall,³ and Clifford J. Woolf¹

¹Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, ²Anesthesiology Pain Research Group, Department of Anesthesiology, Lausanne University Hospital and Institute of Cell Biology and Morphology, Faculty of Biology and Medicine, Lausanne University, 1005 Lausanne, Switzerland, and ³Department of Anatomy and Neuroscience, University of Texas Medical Branch, Galveston, Texas 77555-1069

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.

Key words: caspase-3; glutamate excitotoxicity; GABA; spinal inhibition; dorsal horn; neuropathic pain

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Received April 18, 2005; revised June 22, 2005; accepted June 23, 2005.

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