Inhibition of rapid heat responses in nociceptive primary sensory neurons of rats by vanilloid receptor antagonists.
Academic Article
Overview
abstract
Recent studies demonstrated that heat-sensitive nociceptive primary sensory neurons respond to the vanilloid receptor (VR) agonist capsaicin, and the first cloned VR is a heat-sensitive ion channel. Therefore we studied to what extent heat-evoked currents in nociceptive dorsal root ganglion (DRG) neurons can be attributed to the activation of native vanilloid receptors. Heat-evoked currents were investigated in 89 neurons acutely dissociated from adult rat DRGs as models for their own terminals using the whole cell patch-clamp technique. Locally applied heated extracellular solution (effective temperature approximately 53 degrees C) rapidly activated reversible and reproducible inward currents in 80% (62/80) of small neurons (< or = 32.5 microm), but in none of nine large neurons (P < 0.001, chi(2) test). Heat and capsaicin sensitivity were significantly coexpressed in this subpopulation of small DRG neurons (P < 0.001, chi(2) test). Heat-evoked currents were accompanied by an increase of membrane conductance (320 +/- 115%; mean +/- SE, n = 7), had a reversal potential of 5 +/- 2 mV (n = 5), which did not differ from that of capsaicin-induced currents in the same neurons (4 +/- 3 mV), and were carried at least by Na(+) and Ca(2+) (pCa(2+) > pNa(+)). These observations are consistent with the opening of temperature-operated nonselective cation channels. The duration of action potentials was significantly higher in heat-sensitive (10-90% decay time: 4.45 +/- 0.39 ms, n = 12) compared with heat-insensitive neurons (2.18 +/- 0.19 ms, n = 6; P < 0.005, Student's t-test), due to an inflection in the repolarizing phase. This property as well as capsaicin sensitivity and small cell size are characteristics of nociceptive DRG neurons. When coadministered with heat stimuli, the competitive VR antagonist capsazepine (1 microM to 1 mM) significantly reduced heat-evoked currents in a dose-dependent manner (IC(50) 13 microM, Hill slope -0.58, maximum effect 75%). Preincubation for 12-15 s shifted the IC(50) by approximately 0.5 log(10) units to an estimated IC(50) of approximately 4 microM. The noncompetitive VR antagonist ruthenium red (5 microM) significantly reduced heat-evoked currents by 33 +/- 6%. The effects of both VR antagonists were rapidly reversible. Our results provide evidence for a specific activation of native VRs in nociceptive primary sensory neurons by noxious heat. The major proportion of the rapid heat-evoked currents can be attributed to the activation of these temperature-operated channels, and noxious heat may be the signal detected by VRs under physiological conditions.
