Chelation of zinc in the extracellular area of the spinal cord, using ethylenediaminetetraacetic acid disodium-calcium salt or dipicolinic acid, inhibits the antinociceptive effect of capsaicin in adult mice

Capsaicin depolarizes primary afferent C-fibers releasing substance P (SP) whose N-terminal metabolites appear to play a role in the development of an tinociception. Because some effects of SP(1-7) are similar to those of zinc , we tested the hypothesis that zinc in the extracellular area plays a role in capsaicin-induced antinociception, as measured using the abdominal stre tch (writhing) assay. Decreases in zinc were achieved by intrathecal (i.t.) injection of membrane-impermeable compounds: ethylenediaminetetraacetic ac id disodium-calcium salt (Ca++ EDTA), a calcium-saturated chelator of dival ent cations, or dipicolinic acid, a zinc chelator. Ten nanomoles of Ca++ ED TA had no effect on writhing at either 90 min or 24 h after injection, yet pretreatment with Ca++ EDTA prevented the development of antinociception 24 h after i.t. injection of either 2.8 nmol of capsaicin or 10 nmol of SP(1- 7). One nanomole of dipicolinic acid injected i.t. also blocked capsaicin- and SP(1-7)-induced antinociception. When injected 24 h after SP(1-7), Ca+ EDTA failed to reverse antinociception. Acute antinociception produced 30 min after injection of SP(1-7) was also blocked when Ca++ EDTA was injected 24 h, but not 60 min, before SP(1-7). Thus, the optimal time of Gate EDTA- induced hyperalgesia (90 min), described previously, did not correspond to that of its inhibitory effect on antinociception (24 h). In contrast, we fo und that the previously described antinociception after an i.t. injection o f zinc (90 min) is greatly attenuated by 24 h. Thus, zinc appears to be nec essary, but may not be sufficient, for the long-term antinociceptive effect of capsaicin, acting downstream from the action of substance P N-terminal metabolites.