Department of Anesthesiology

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HCN1 channels as targets for anesthetic and nonanesthetic propofol analogs in the amelioration of mechanical and thermal hyperalgesia in a mouse model of neuropathic pain.

TitleHCN1 channels as targets for anesthetic and nonanesthetic propofol analogs in the amelioration of mechanical and thermal hyperalgesia in a mouse model of neuropathic pain.
Publication TypeJournal Article
Year of Publication2013
AuthorsTibbs GR, Rowley TJ, R Sanford L, Herold KF, Proekt A, Hemmings HC, Andersen OS, Goldstein PA, Flood PD
JournalJ Pharmacol Exp Ther
Volume345
Issue3
Pagination363-73
Date Published2013 Jun
ISSN1521-0103
KeywordsAlgorithms, Anesthetics, Anesthetics, Intravenous, Animals, Behavior, Animal, Biological Availability, Cyclic Nucleotide-Gated Cation Channels, DNA, Complementary, Electrophysiological Phenomena, Female, Hot Temperature, Humans, Hyperalgesia, Indicators and Reagents, Lipid Bilayers, Mice, Mice, Inbred C57BL, Neuralgia, Oocytes, Patch-Clamp Techniques, Potassium Channels, Propofol, Xenopus
Abstract

Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarization-activated, cyclic nucleotide-regulated (HCN)-mediated IH pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-di-iso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA(A) receptor (GABA(A)-R) potentiation, and general anesthesia. Thus, 2,6- and 2,4-di-tertbutylphenol (2,6- and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6- and 2,4-di-sec-butylphenol (2,6- and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA(A)-R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA(A)-R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

DOI10.1124/jpet.113.203620
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID23549867
PubMed Central IDPMC3657108
Grant ListGM021342 / GM / NIGMS NIH HHS / United States
GM021342-35S1 / GM / NIGMS NIH HHS / United States
GM58055 / GM / NIGMS NIH HHS / United States
R01 GM058055 / GM / NIGMS NIH HHS / United States