Rises in [Ca2+]i mediate capsaicin- and proton-induced heat sensitization of rat primary nociceptive neurons

Eur J Neurosci. 1999 Sep;11(9):3143-50. doi: 10.1046/j.1460-9568.1999.00734.x.


Capsaicin (CAPS) as well as acidic pH induces Ca2+ influx in a subset of rat dorsal root ganglion neurons. Here we show that CAPS as well as three different approaches to induce experimental tissue acidification (phosphate buffered solution pH 5.4, CO2-gassed solution pH 6.1 and NPE-caged protons) yielded a transient heat sensitization of peripheral nociceptive terminals in rat skin in vitro. The heat sensitization induced by CAPS (1 microM) could be prevented by preloading the neurons with the neuroprotective calcium chelator BAPTA-AM (1 mM). However, this pretreatment had no effect on the sensitization following exposure to acidic solutions (pH 5.4 and pH 6.1). Therefore, the membrane-permeant proton buffer SNARF-AM (200 microM) was used together with BAPTA-AM in order to prevent changes in intracellular pH. Under these conditions heat sensitization by low pH did not occur. To investigate the underlying membrane mechanisms, current recordings together with simultaneous calcium measurements using FURA-2 were performed in neurons isolated from rat dorsal root ganglia. In a subset of these neurons, an increase in [Ca2+]i and concomitant facilitation of heat-activated ionic currents was observed after application of CAPS as well as pH 5.6. Rises in [Ca2+]i thus appear to play an essential role in plastic changes not only of central neurons but also of peripheral nociceptive terminals which may account for heat hyperalgesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium / physiology*
  • Capsaicin / pharmacology*
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Fluorescent Dyes
  • Fluorometry
  • Fura-2
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology
  • Hot Temperature / adverse effects*
  • Hydrogen-Ion Concentration
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Nerve Fibers / physiology
  • Neurons, Afferent / drug effects*
  • Nociceptors / drug effects*
  • Patch-Clamp Techniques
  • Rats
  • Skin / innervation
  • Stimulation, Chemical
  • Ultraviolet Rays


  • Chelating Agents
  • Fluorescent Dyes
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid
  • Capsaicin
  • Calcium
  • Fura-2