Role of [Ca]i in the ATP-Induced Heat Sensitization Process of Rat Nociceptive Neurons

Kress, M. and S. Guenther. Role of [Ca]i in the ATP-induced heat sensitization process of rat nociceptive neurons. J. Neurophysiol. 81: 2612–2619, 1999. In inflamed tissue, nociceptors show increased sensitivity to noxious heat, which may account for heat hyperalgesia. In unmyelinated nociceptive afferents in rat skin in vitro, a drop of heat threshold and an increase in heat responses were induced by experimental elevation of intracellular calcium ([Ca]i) levels with the calcium ionophore ionomycin (10 mM). Similar results were obtained in experiments employing [Ca]i release from preloaded “caged calcium” (NITR-5/AM) via UV photolysis. In both cases, sensitization was prevented by preventing rises in [Ca]i with the membrane-permeant calcium chelator BAPTA-AM (1 mM). No pronounced change of mechanical sensitivity was observed. Heat-induced membrane currents (Iheat) were investigated with patch-clamp recordings, and simultaneous calcium measurements were performed in small sensory neurons isolated from adult rat dorsal root ganglia (DRG). Ionomycin-induced rises in [Ca]i resulted in reversible sensitization of Iheat. In the same subset of DRG neurons, the endogenous algogen ATP (100 mM) was used to elevate [Ca]i, which again resulted in significant sensitization of Iheat. In correlative recordings from the skin–nerve preparation, ATP induced heat sensitization of nociceptors, which again could be blocked by preincubation with BAPTA-AM. Rises in [Ca]i in response to inflammatory mediators, e.g., ATP, thus appear to play a central role in plastic changes of nociceptors, which may account for hypersensitivity of inflamed tissue.