Zinc in the extracellular area of the central nervous system is necessary for the development of kainic acid-induced persistent hyperalgesia in mice

Kainic acid produces a persistent hyperalgesia when injected intraperitonea lly (i.p.) in the rat or mouse. At higher doses than those needed to influe nce nociception, kainic acid induces seizures and translocation of histolog ically reactive zinc in the hippocampus. We tested the hypothesis that zinc , localized in a population of small diameter primary afferent neurons, pla ys a role in kainic acid-induced hyperalgesia similar to that in the hippoc ampus where zinc translocation accompanies kainic acid-induced seizures. Th e importance of zinc in the extracellular area was assessed by the influenc e of compounds that chelate divalent cations (disodium calcium ethylene dia minetetraacetate (CaEDTA)) or zinc (dipicolinic acid (DPA)) on kainic acid- induced hyperalgesia. When measured using the tail flick assay, thermal hyp eralgesia was blocked by pretreatment intrathecally (i.t.) with either 10 n mol of NaCaEDTA or 1 nmol of DPA, drugs whose distribution is limited to th e extracellular area. Injection of 10 ng zinc chloride i.t, had no long-ter m effect on nociception or on kainic acid-induced hyperalgesia. Whether zin c is translocated in response to a hyperalgesic dose of kainic acid was det ermined using the zinc selective dye, N-(6-methoxy-8-quinolyl)-para-toluene nsulfonmide (TSQ), which produces a delicate stain in the neuropil of the m ouse spinal cord as well as a dense stain in the hippocampus. Injection of a hyperalgesic dose of kainic acid failed to alter TSQ fluorescence in eith er the spinal cord or hippocampus, in contrast to the distinct bleaching of TSQ in the hippocampus 24 h after a convulsant dose of kainic acid. Togeth er these data suggest that, while not translocated, zinc in the extracellul ar area is necessary but not sufficient for the development of kainic acid- induced hyperalgesia. (C) 2000 International Association for the Study of P ain. Published by Elsevier Science B.V. All rights reserved.