Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.
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.
Scholz
Joachim
J
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. scholz.joachim@mgh.harvard.edu
Broom
Daniel C
DC
Youn
Dong-Ho
DH
Mills
Charles D
CD
Kohno
Tatsuro
T
Suter
Marc R
MR
Moore
Kimberly A
KA
Decosterd
Isabelle
I
Coggeshall
Richard E
RE
Woolf
Clifford J
CJ
D000344:Afferent Pathways / Q000503:physiopathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009437:Neuralgia / Q000523:psychology; D009474:Neurons; D020671:Posterior Horn Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries*; D013116:Spinal Cord / Q000503:physiopathology; D013569:Synapses; D014947:Wounds and Injuries / Q000503:physiopathology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; D020169:Caspases