Journal of Neurophysiology, Vol 75, Issue 1 1-10, Copyright © 1996 by APS

ARTICLES

Diltiazem blocks the PH-induced excitation of rat nociceptors together with their mechanical and electrical excitability in vitro

H. Wegner, P. W. Reeh, S. Brehm, H. W. Kreysel and K. H. Steen
Universitatshautklinik und Poliklinik der Universitat Bonn, Germany.

1. The effect of the calcium channel antagonist diltiazem on pH-induced sustained nociceptor excitation was investigated in a rat skin-saphenous nerve preparation, in vitro, where receptive fields of identified and isolated single fibers were superfused at the corium side with controlled solutions to assess their chemosensitivity. 2. Unmyelinated mechano-heat sensitive ("polymodal") C fiber terminals (n = 78) were superfused with a CO2-saturated synthetic interstitial fluid (CO2-SIF, pH 6.1). Fibers responding to this acid pH condition (n = 60; 77%) were further stimulated for > or = 30 min and additionally treated with diltiazem in various concentrations (10(-6)-10(-3) M) during the middle 10-min period. Usually only one concentration of diltiazem was applied per fiber, although in some cases diltiazem was applied repeatedly and in increasing concentrations. 3. Diltiazem dose-dependently and reversibly reduced the pH-induced sustained nociceptor discharge to a significant degree or completely abolished it. With higher concentrations, both the relative number of units affected and the average amount of suppression were enhanced. The half-maximal blocking concentration (IC50) was estimated to 1.1.10(-4) M diltiazem, the half-maximal concentration for gradual suppression of the pH response was 2.10(-5) M diltiazem. 4. Also, the delay of onset of the suppressive effect decreased with higher diltiazem concentrations. After diltiazem, a partial recovery of the pH-induced discharge was achieved within 10 min depending on the degree of suppression. 5. Before, after, and sometimes during the superfusion, the mechanical (von Frey) thresholds were determined and found to be significantly increased after partial wash out of diltiazem (10(-4) and 10(-3) M; P < 0.006 and P < 0.008, respectively). After 10(-3) M diltiazem superfusion (and 10 min of wash-out), the responsiveness to mechanical stimulation of the majority of the fibers was still totally lost. 6. Heat thresholds were still found to be significantly increased after treatment with diltiazem at 10(-3) and 10(-4) M concentrations (and 10 min of wash out), but appeared unchanged after wash out of lower concentrations. 7. In five mechano-heat-sensitive C fibers, electrical stimulation via a microelectrode placed in the receptive field was used to demonstrate a diltiazem-dose-dependent (10(-5), 10(-4), 10(-3) M) progressive retardation of the nerve conduction velocity and an increase of the electrical threshold. Superfusion for 6 min of diltiazem 10(-5) M was sufficient to block axonal conduction as well as mechanosensitivity, which both recovered synchronously during wash out. 8. It can be concluded from the results that the suppressive effect of diltiazem on pH-induced nociceptor excitation can be explained by a use-dependent axonal block, comparable with the action of local anesthetics and affecting all modalities of sensory responsiveness. 9. The findings provide no indication that a transformed calcium channel specifically sensitive to diltiazem is involved in pH-induced sustained nociceptor excitation.

This article has been cited by other articles:

				K. Stecina, J. Quevedo, and D. A. McCrea Parallel reflex pathways from flexor muscle afferents evoking resetting and flexion enhancement during fictive locomotion and scratch in the cat J. Physiol., November 15, 2005; 569(1): 275 - 290. [Abstract] [Full Text] [PDF]

				C. Gruneberg, J. Duysens, F. Honegger, and J.H.J. Allum Spatio-Temporal Separation of Roll and Pitch Balance-Correcting Commands in Humans J Neurophysiol, November 1, 2005; 94(5): 3143 - 3158. [Abstract] [Full Text] [PDF]

				R. W. Putnam, J. A. Filosa, and N. A. Ritucci Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons Am J Physiol Cell Physiol, December 1, 2004; 287(6): C1493 - C1526. [Abstract] [Full Text] [PDF]

				D. A McCrea Spinal circuitry of sensorimotor control of locomotion J. Physiol., May 15, 2001; 533(1): 41 - 50. [Abstract] [Full Text] [PDF]

				M-C Perreault, S J Shefchyk, I Jimenez, and D A McCrea Depression of muscle and cutaneous afferent-evoked monosynaptic field potentials during fictive locomotion in the cat J. Physiol., December 15, 1999; 521(3): 691 - 703. [Abstract] [Full Text] [PDF]

				U. Ziemann, R. Chen, L. G. Cohen, and M. Hallett Dextromethorphan decreases the excitability of the human motor cortex Neurology, November 1, 1998; 51(5): 1320 - 1324. [Abstract] [Full Text] [PDF]

				S. M. Henry, J. Fung, and F. B. Horak EMG Responses to Maintain Stance During Multidirectional Surface Translations J Neurophysiol, October 1, 1998; 80(4): 1939 - 1950. [Abstract] [Full Text] [PDF]

				K. D. Pfann, R. D. Penn, K. M. Shannon, and D. M. Corcos Pallidotomy and bradykinesia: Implications for basal ganglia function Neurology, September 1, 1998; 51(3): 796 - 803. [Abstract] [Full Text] [PDF]