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The Journal of Neuroscience, August 1, 2002, 22(15):6325-6330

BRIEF COMMUNICATION
Endothelin-1 (ET-1) Selectively Enhances the Activation Gating of Slowly Inactivating Tetrodotoxin-Resistant Sodium Currents in Rat Sensory Neurons: A Mechanism for the Pain-Inducing Actions of ET-1

Zhongren Zhou^{1, *}, Gudarz Davar^{1, *}, and Gary Strichartz^{1, 2}

¹ Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, and ² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

Endothelin-1 (ET-1) causes pain through activation of nociceptors, by either direct depolarization or increased excitability. Here we examined the effect of ET-1 on nociceptor-associated tetrodotoxin-resistant (TTX-R) sodium currents using whole-cell voltage clamp of acutely dissociated rat dorsal root ganglion (DRG) neurons. DRG neurons that responded had enhanced activation gating when exposed to 10 nM ET-1, as determined by significant shifts in their average activation midpoint potentials (E_0.5 = 8.0 ± 0.5 mV) when compared with control (E_0.5 = 2.2 ± 0.4 mV; n = 6) and ET-1 unresponsive cells (E_0.5 = 3.2 ± 0.2 mV). ET-1 also modified the availability of TTX-R channels, as determined by negative shifts in the average midpoint potential for inactivation of ET-1 responsive cells when compared with controls. These actions of ET-1 occurred predominantly in cells with more slowly inactivating TTX-R currents. Both time-to-peak current and inactivation time constants were shortened by ET-1 in responsive cells. Previous exposure of cells to the endothelin-A (ET_A) receptor antagonist BQ-123 (1 µM) prevented ET-1-induced shifts in TTX-R activation. In contrast to changes in TTX-R, ET-1 did not modify tetrodotoxin-sensitive currents recorded from DRG neurons. These results demonstrate that the algogenic peptide ET-1 induces ET_A receptor-mediated, hyperpolarizing shifts in the voltage-dependent activation of TTX-R Na⁺ channels, a potential mechanism for selective excitation by ET-1 of nociceptors that we observed in vivo.

Key words: nociception; excitability; G-protein-coupled receptor; sodium channel; hyperalgesia, dorsal root ganglion neurons

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^* Z.Z. and G.D. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22156325-06$05.00/0

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