MANIPULATIONS OF ZINC IN THE SPINAL-CORD, BY INTRATHECAL INJECTION OFZINC-CHLORIDE, DISODIUM-CALCIUM-EDTA, OR DIPICOLINIC ACID, ALTER NOCICEPTIVE ACTIVITY IN MICE

Zinc is concentrated in the dorsal horn of the spinal cord and has bee n proposed to alter excitability of primary afferent C-fibers, structu res believed to be important in nociceptive transmission. Based on the inhibitory effect of zinc on the activity of various other neurotrans mitters that play a role in nociception, we tested the hypothesis that zinc modulates pain transmission. To test this, we examined the effec t of exogenous zinc, administered intrathecally (i.t.), on nociception in the mouse. We also assessed the impact of decreased concentrations of endogenously occurring zinc in the extracellular fluid brought abo ut by an i.t. injection of either ethylenediaminetetraacetic acid diso dium-calcium salt (Ca(++)EDTA), a calcium-saturated, membrane-impermea ble chelator of divalent cations, or of dipicolinic acid, a zinc chela tor. Injection of zinc produced a dose-related antinociceptive effect, optimal at 90 min in the writhing assay, but had no effect on tail-fl ick response latencies. In contrast, injection of either Ca(++)EDTA or dipicolinic acid produced a dose-related hyperalgesia in the tail-fli ck assay at 90 min after injection. Responses induced in the writhing assay were unaffected by Ca(++)EDTA. Although zinc had no effect on th ermal nociception, the hyperalgesic effect of Ca(++)EDTA was antagoniz ed by coadministration of Ca(++)EDTA with zinc. Similarly, the antinoc iceptive effect of zinc on writhing responses was attenuated when coad ministered with Ca(++)EDTA. Zinc also inhibited primary afferent C-fib er activity because 10 ng of zinc i.t. inhibited the behavioral respon se induced by injection i.t. of 1 nmol of capsaicin. Neither zinc nor Ca(++)EDTA altered writhing or tail-flick latencies, respectively, whe n injected intracerebroventricularly. These findings support the hypot hesis that endogenous zinc, localized in the dorsal horn of the spinal cord, plays a role in the regulation of pain.