Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons
1 Discovery Neuroscience and 2 Chemical and Screening Sciences, Wyeth Research, Princeton, New Jersey Submitted 10 August 2006; accepted in final form 18 March 2007 Hyperpolarization-activated cyclic nucleotidegated (HCN) channels are responsible for the functional hyperpolarization-activated curre...
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Published in | Journal of neurophysiology Vol. 97; no. 5; p. 3713 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Am Phys Soc
01.05.2007
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Subjects | |
Online Access | Get full text |
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Summary: | 1 Discovery Neuroscience and 2 Chemical and Screening Sciences, Wyeth Research, Princeton, New Jersey
Submitted 10 August 2006;
accepted in final form 18 March 2007
Hyperpolarization-activated cyclic nucleotidegated (HCN) channels are responsible for the functional hyperpolarization-activated current ( I h ) in dorsal root ganglion (DRG) neurons, playing an important role in pain processing. We found that the known analgesic loperamide inhibited I h channels in rat DRG neurons. Loperamide blocked I h in a concentration-dependent manner, with an IC 50 = 4.9 ± 0.6 and 11.0 ± 0.5 µM for large- and small-diameter neurons, respectively. Loperamide-induced I h inhibition was unrelated to the activation of opioid receptors and was reversible, voltage-dependent, use-independent, and was associated with a negative shift of V 1/2 for I h steady-state activation. Loperamide block of I h was voltage-dependent, gradually decreasing at more hyperpolarized membrane voltages from 89% at 60 mV to 4% at 120 mV in the presence of 3.7 µM loperamide. The voltage sensitivity of block can be explained by a loperamide-induced shift in the steady-state activation of I h . Inclusion of 10 µM loperamide into the recording pipette did not affect I h voltage for half-maximal activation, activation kinetics, and the peak current amplitude, whereas concurrent application of equimolar external loperamide produced a rapid, reversible I h inhibition. The observed loperamide-induced I h inhibition was not caused by the activation of peripheral opioid receptors because the broad-spectrum opioid receptor antagonist naloxone did not reverse I h inhibition. Therefore we suggest that loperamide inhibits I h by direct binding to the extracellular region of the channel. Because I h channels are involved in pain processing, loperamide-induced inhibition of I h channels could provide an additional molecular mechanism for its analgesic action.
Address for reprint requests and other correspondence: D. Vasilyev, Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543-8000 (E-mail: vasylyd{at}wyeth.com ) |
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ISSN: | 0022-3077 1522-1598 |
DOI: | 10.1152/jn.00841.2006 |