Pungent General Anesthetics Activate Transient Receptor Potential-A1 to Produce Hyperalgesia and Neurogenic Bronchoconstriction

Department of Anesthesia, University of California, San Francisco, California 94143-0427, USA.
Anesthesiology (Impact Factor: 6.17). 06/2010; 112(6):1452-63. DOI: 10.1097/ALN.0b013e3181d94e00
Source: PubMed

ABSTRACT Volatile anesthetics such as isoflurane and halothane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anesthesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of peripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways.
To test the hypothesis that irritant inhaled anesthetics activate the excitatory ion-channel transient receptor potential (TRP)-A1 and thereby contribute to hyperalgesia and irritant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our functional experiments, we used models of isolated guinea pig bronchi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice.
Irritant inhaled anesthetics activate TRPA1 expressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonirritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction.
General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting.

  • Source
    • "Flufenamic acid e Hu et al., 2010 Flurbiprofen Hu et al., 2010 Indomethacin Hu et al., 2010 Isoflurane Eilers et al., 2010 Ketoprofen Hu et al., 2010 Mefenamic acid Hu et al., 2010 Niflumic acid Hu et al., 2010 Propofol Lee et al., 2008; Fischer et al., 2010 a Camphor activates TRPV1 and TRPV3 but inhibits TRPA1 (Xu et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Approximately 20 of the 30 mammalian transient receptor potential (TRP) channel subunits are expressed by specific neurons and cells within the alimentary canal. They subserve important roles in taste, chemesthesis, mechanosensation, pain and hyperalgesia and contribute to the regulation of gastrointestinal motility, absorptive and secretory processes, blood flow, and mucosal homeostasis. In a cellular perspective, TRP channels operate either as primary detectors of chemical and physical stimuli, as secondary transducers of ionotropic or metabotropic receptors, or as ion transport channels. The polymodal sensory function of TRPA1, TRPM5, TRPM8, TRPP2, TRPV1, TRPV3 and TRPV4 enables the digestive system to survey its physical and chemical environment, which is relevant to all processes of digestion. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 contribute to the absorption of Ca²⁺ and Mg²⁺, respectively. TRPM7 participates in intestinal pacemaker activity, and TRPC4 transduces muscarinic acetylcholine receptor activation to smooth muscle contraction. Changes in TRP channel expression or function are associated with a variety of diseases/disorders of the digestive system, notably gastro-esophageal reflux disease, inflammatory bowel disease, pain and hyperalgesia in heartburn, functional dyspepsia and irritable bowel syndrome, cholera, hypomagnesemia with secondary hypocalcemia, infantile hypertrophic pyloric stenosis, esophageal, gastrointestinal and pancreatic cancer, and polycystic liver disease. These implications identify TRP channels as promising drug targets for the management of a number of gastrointestinal pathologies. As a result, major efforts are put into the development of selective TRP channel agonists and antagonists and the assessment of their therapeutic potential.
    Pharmacology [?] Therapeutics 03/2011; 131(1):142-70. DOI:10.1016/j.pharmthera.2011.03.006 · 7.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mount Giluwe is a large extinct dome-shaped volcano built up mainly of thin flows of mafic lava rich in potassium. It rises from 2100 m to 4368 m above sea level. During the Pleistocene, it was covered by an ice cap which extended as low as the 3200 to 3500 m level. Although the volcano is dissected by a radial drainage system, cones, craters, lava mounds, lava flow surfaces, and volcanic debris, slopes are well-preserved below the glaciated area. Above this, the original volcanic landforms have been destroyed or modified by glacial activity, and well-preserved lateral moraines, groups of recessional moraines, glacial valleys, cirques, rock basins, and roches moutonnées are present. During the period of maximum glaciation, valley glaciers as thick as 400 m protruded from the edge of the ice cap down preexisting valleys and terminated at elevations between 2750 and 3000 m. On the northeastern side of the volcano, fluvioglacial deposits derived from the valley glaciers formed fans extending onto the Kaugel plain, which is incised 40 m by the present Kaugel River. This incision is almost entirely postglacial. Palagonitic breccia and scoria overlie, and are interlayered with, normal lava flows in the summit area of the volcano. They indicate that some subglacial volcanic activity took place and that there were probably at least two different periods of glaciation. The last glacial period (contemporaneous with the Würm glaciation of Europe and the Wisconsin glaciation of North America) was the more extensive, covering about 190 km2. It was responsible for the development of the existing glacial landforms. Most of the volcanic landforms are older than this last glaciation.
    Geological Society of America Bulletin 01/1971; 82(6). DOI:10.1130/0016-7606(1971)82[1605:VAGLOM]2.0.CO;2 · 4.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A review. This review discusses the TRPA1 Channel as emerging target for analgesics and anti-inflammatory agents. [on SciFinder(R)]
    Journal of Medicinal Chemistry 04/2010; 53(14):5085-107. DOI:10.1021/jm100062h · 5.48 Impact Factor
Show more