Abstract/Details

The effects of volatile general anesthetics on TRPV1 and TRPA1, two transient receptor potential ion channels in the peripheral pain transduction pathway


2006 2006

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Abstract (summary)

TRPV1 is a sensory neuron-specific ion channel and a polymodal detector of pain-producing chemical and physical stimuli. Sensitization or activation of TRPV1 leads to thermal, chemical or mechanical hypersensitivity. TRPA1 is another ion channel that senses pungent chemicals and is co-localized with TRPV1. TRPA1 is activated by isothiocyanates, garlic, cinnamon, and volatile environmental pollutants. Volatile general anesthetics (VGAs) are a diverse group of drugs with shared ability to suppress CNS activity through modulation of ion channels involved in synaptic transmission. Many VGAs are also chemical irritants, pungent to inhale, and activate capsaicin-sensitive C-fibers.

We therefore tested the ability of VGAs to modulate TRPV1 and TRPA1 in an expression system, cultured sensory neurons and mice (TRPA1). We also studied whether activation of either receptor correlated with anesthetic pungency.

Results. Isoflurane enhanced the response of TRPV1 to agonists and lowered the heat activation threshold. These effects were greater when receptors were sensitized by PKC-mediated phosphorylation. All VGAs tested (isoflurane, desflurane, sevoflurane, halothane, methoxyflurane) enhanced responses to protons, and the degree of activation correlated with pungency. Mechanistically, we hypothesize that VGAs regulate TRPV1 by direct allosteric actions since effects were preserved in excised patches from nodose TRPV1-expressing neurons. Effects of VGAs on TRPA1 were even more marked. Pungent VGAs directly activated the receptor and enhanced response to mustard oil (MO) at low concentrations. In contrast, non-pungent VGAs alone had no effect, and blocked MO-evoked activation. However, all VGAs regardless of pungency blocked MO effects at higher concentrations. We postulate that this is due to VGAs blocking the channel pore. Finally, mice anesthetized with isoflurane, a pungent VGA, had greater MO-induced ear swelling than those anesthetized with sevoflurane, a non-pungent agent, correlating well with our in vitro data at low MO concentrations.

Conclusions. (1) VGAs can modulate both TRPV1 and TRPA1. (2) Sensitization or activation of either receptor by VGAs may increase neurogenic inflammation and pain in tissues injured by surgical intervention. (3) TRPA1 and perhaps TRPV1 may sense the pungency of certain VGAs. (4) Pharmacologic blockade of either receptor may be a useful strategy for reducing postoperative inflammation and pain associated with surgery.

Indexing (details)


Subject
Pharmacology;
Anesthesia;
Neurons;
Pain management
Classification
0419: Pharmacology
Identifier / keyword
Health and environmental sciences; General anesthetics; Ion channels; Peripheral pain
Title
The effects of volatile general anesthetics on TRPV1 and TRPA1, two transient receptor potential ion channels in the peripheral pain transduction pathway
Author
Cornett, Paul Matthew
Number of pages
168
Publication year
2006
Degree date
2006
School code
0544
Source
DAI-B 68/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Advisor
Ahern, Gerard P.
University/institution
Georgetown University Medical Center
University location
United States -- District of Columbia
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3260195
ProQuest document ID
304934923
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304934923/abstract
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