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: 5.88).
06/2010; 112(6):1452-63. DOI: 10.1097/ALN.0b013e3181d94e00
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.
Available from: PubMed Central
- "In contrast to analgesics which relieve pain without compromising other forms of sensation, anesthetics eliminate sensation generally and reversibly by inhibiting voltage-gated Na+ channels [185, 186]. Interestingly, both local and general anesthetics activate nociceptive ion channels including TRPV1 and TRPA1 to enhance pain and inflammation [187-194]. Lidocaine activates TRPV1 through a mechanism similar to that of capsaicin . Depletion of PIP2 and a point mutation disrupting the PIP2 interaction site at the C-terminus of TRPV1 also attenuate the excitatory effect of lidocaine on TRPV1 . "
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ABSTRACT: Chronic pain affects billions of lives globally and is a major public health problem in the United States. However, pain management is still a challenging task due to a lack of understanding of the fundamental mechanisms of pain. In the past decades transient receptor potential (TRP) channels have been identified as molecular sensors of tissue damage and inflammation. Activation/sensitization of TRP channels in peripheral nociceptors produces neurogenic inflammation and contributes to both somatic and visceral pain. Pharmacological and genetic studies have affirmed the role of TRP channels in multiple forms of inflammatory and neuropathic pain. Thus pain-evoking TRP channels emerge as promising therapeutic targets for a wide variety of pain and inflammatory conditions.
Available from: Charlotte Dubois
- "Our results establish a link between cold sensation and VA administration, since we show that VAs directly activate the TRPM8 cold receptor. Recently, it has been shown that 'pungent' inhalation general anaesthetics (which are known to excite peripheral nociceptors), namely isoflurane and desflurane, activate TRP-member TRPA1 and sensitize the TRPV1 heat receptor to its agonists, capsaicin and protons (Cornett et al., 2008;Matta et al., 2008;Eilers et al., 2010), but do not affect the TRPM8 cold receptor. These authors concluded that the pro-nociceptive effects of these anaesthetics combined with surgical tissue damage may specifically contribute to postoperative pain and inflammation, as well as producing airway irritation. "
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ABSTRACT: The mechanisms by which volatile general anaesthetics (VAs) produce a depression of central nervous system are beginning to be better understood, but little is known about a number of side effects. Here, we show that the cold receptor, TRPM8, is complexly modulated by clinical concentration of VAs in dorsal root ganglion neurons and HEK-293 cells heterologously expressing TRPM8. VAs produced transient enhancement of TRPM8 via a depolarizing shift of its activation towards physiological membrane potentials, followed by a sustained TRPM8 inhibition. Stimulatory action of VAs engaged molecular determinants distinct from those used by the TRPM8 agonist. Transient TRPM8 activation by VAs could explain such side effects as inhibition of respiratory drive, shivering and cooling sensation during the beginning of anaesthesia, whereas the second phase of VA action associated with sustained TRPM8 inhibition may be responsible for hypothermia. Consistent with this, both hypothermia and inhibition of respiratory drive induced by VAs are partially abolished in TRPM8-null animals. Thus, we propose TRPM8 as a new clinical target for diminishing common and serious complications of general anaesthesia.
Available from: Andreas Leffler
- "In a clinical perspective, this study complements a growing evidence that most general and local anesthetics as well as some analgesics activate or sensitize nociceptors via TRPA1 and/or TRPV1 [15,31,36-39]. Systemically applied substances, like general anesthetics and analgesics could employ TRPA1 to regulate or promote post-operative pain and inflammation. "
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ABSTRACT: Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na⁺ channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P₂-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1.
Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs.
The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.
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