A-fiber sensory input induces neuronal cell death in the dorsal horn of the adult rat spinal cord

Excitoxicity due to excessive synaptic glutamate release is featured in man y neurological conditions in which neuronal death occurs. Whether activatio n of primary sensory pathways can ever produce sufficient over-activity in secondary sensory neurons in the dorsal horn of the spinal cord to induce c ell death, however, has not been determined. In this study, we asked whethe r activity in myelinated afferents (A fibers), which use glutamate as a tra nsmitter, can induce cell death in the dorsal horn. Using stereological est imates of neuron numbers from electron microscopic sections, we found that stimulation of A-fibers in an intact sciatic nerve at 10 Hz, 20 Hz, and 50 Hz in 10-minute intervals at a stimulus strength that activates both A beta and A delta fibers resulted in the loss of 25% of neurons in lamina III, t he major site of termination of large A beta fibers, but not in lamina I, w here A delta fibers terminate. Furthermore, sciatic nerve lesions did not r esult in detectable neuron loss, but activation of A fibers in a previously sectioned sciatic nerve did cause substantial cell death not only in lamin a III but also in laminae I and II. The expansion of the territory of A-fib er afferent-evoked cell death is likely to reflect the sprouting of the fib ers into these laminae after peripheral nerve injury. The data show, theref ore, that primary afferent A-fiber activity can cause neuronal cell death i n the dorsal horn with an anatomical distribution that depends on whether i ntact or injured fibers are activated. Stimulation-induced cell death poten tially may contribute to the development of persistent pain. (C) 2001 Wiley -Liss, Inc.