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

Abstract

Kainic acid produces a persistent hyperalgesia when injected intraperitoneally (i.p.) in the rat or mouse. At higher doses than those needed to influence nociception, kainic acid induces seizures and translocation of histologically reactive zinc in the hippocampus. We tested the hypothesis that zinc, localized in a population of small diameter primary afferent neurons, plays a role in kainic acid-induced hyperalgesia similar to that in the hippocampus where zinc translocation accompanies kainic acid-induced seizures. The importance of zinc in the extracellular area was assessed by the influence of compounds that chelate divalent cations (disodium calcium ethylene diaminetetraacetate (CaEDTA)) or zinc (dipicolinic acid (DPA)) on kainic acid-induced hyperalgesia. When measured using the tail flick assay, thermal hyperalgesia was blocked by pretreatment intrathecally (i.t.) with either 10 nmol of NaCaEDTA or 1 nmol of DPA, drugs whose distribution is limited to the extracellular area. Injection of 10 ng zinc chloride i.t. had no long-term effect on nociception or on kainic acid-induced hyperalgesia. Whether zinc is translocated in response to a hyperalgesic dose of kainic acid was determined using the zinc-selective dye, N-(6-methoxy-8-quinolyl)-para-toluenensulfonamide (TSQ), which produces a delicate stain in the neuropil of the mouse 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 either 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. Together these data suggest that, while not translocated, zinc in the extracellular area is necessary but not sufficient for the development of kainic acid-induced hyperalgesia.