General Anesthetics Sensitize the Capsaicin Receptor Transient Receptor Potential V1

Abstract

General anesthetics (GAs) are central nervous system depressants that render patients unresponsive to external stimuli. In contrast, many of these agents are also known to stimulate peripheral sensory nerves, raising the possibility that they may exacerbate tissue inflammation. We have found that pungent GAs excite sensory neurons by directly activating the transient receptor potential (TRP) A1 ion channel. Here, we show that GAs also sensitize the capsaicin receptor TRPV1, a key ion channel expressed in nociceptive neurons. Clinically relevant concentrations of isoflurane, sevoflurane, enflurane, and desflurane sensitize TRPV1 to capsaicin and protons and reduce the threshold for heat activation. Furthermore, isoflurane directly activates TRPV1 after stimulation of protein kinase C. Likewise, isoflurane excites TRPV1 and sensory neurons during concomitant application of bradykinin, a key inflammatory mediator formed during tissue injury. Thus, GAs can enhance the activation of TRPV1 that occurs during surgically induced tissue damage. These results support the hypothesis that some GAs, through direct actions at TRP channels, increase postsurgical pain and inflammation.

Complex modulation of the cold receptor TRPM8 by volatile anaesthetics and its role in complications of general anaesthesia

“…7D). Given that of the two other VA-sensitive TRP members, TRPV1 is not expressed in these neurons and TRPA1 is not sensitive to capsazepine Cornett et al, 2008;Eilers et al, 2010), this provides additional confirmation of the involvement of TRPM8 in the observed effects (Simon and Liedtke, 2008). Moreover, as in HEK M8 cells, prolonged exposure of mentholresponding DRG neurons to halothane after the initial current activation, caused pronounced current inhibition (Fig.…”

“…Enhancement of the activity of inhibitory ionotropic receptors (Lobo and Harris, 2005;Zeller et al, 2008), depression of the excitatory ionotropic receptors (Yamakura et al, 2001), potentiation of the 2P-domain K + channels (Patel and Honore, 2001), inhibition of voltage-gated Na + channels (Hemmings, 2009) and of the transient receptor potential (TRP) family member TRPC5 (Bahnasi et al, 2008) probably all contribute to the central clinically relevant anaesthetic effects, whereas the action of the same VAs on other ion channels might, at least in part, be responsible for their numerous adverse effects (Stachnik, 2006;Bovill, 2008). Indeed, activation of TRP member TRPA1 by the 'pungent' VAs (those that are known to excite peripheral nociceptive neurons), isoflurane and desflurane Cornett et al, 2008;Eilers et al, 2010), and sensitization of TRPV1 to its agonists, capsaicin and protons Eilers et al, 2010), might contribute to postoperative pain and inflammation, as well as producing airway irritation. Hypersensitivity to cold temperatures and a decreased shivering threshold are also common complications observed after administering VAs (Kurz et al, 1997;Kurz, 2008;Sessler, 2008), suggesting that at least some of their representatives might sensitize peripheral cold receptors.…”

Distinct Modulations of Human Capsaicin Receptor by Protons and Magnesium through Different Domains

“…Noxious heat (Ͼ42°C), acid, and capsaicin, a pungent natural product from chili peppers, all activate TRPV1 to elicit burning pain (1,4). Functional synergism among modalities allows TRPV1 to summate different types of subthreshold stimuli and produce a robust response (1,5,6). The extent of TRPV1 activation by one or a combination of stimuli determines the intensity of evoked pain (7)(8)(9)(10)(11)(12).…”

Sensitization of Nociceptive Ion Channels by Inhaled Anesthetics—A Pain in the Gas?

“…In fact, TRPV1-deficient mice do not develop thermal hyperalgesia in response to inflammation. Another important effect demonstrated in the article by Cornett et al (2008) that fits nicely into the current picture of TRPV1 is that PKC activation (or activation of bradykinin receptors) can enhance the action of IGAs on TRPV1.…”

“…In their elegant study, Cornett et al (2008) demonstrate that IGAs are another class of substances that can sensitize TRPV1 to activation, not only by capsaicin but also by low pH and heat. The effect of isoflurane (ISO) on TRPV1 channels is to shift the dose-response curve (in ligand-gated ion channels, this is essentially akin to the activation curve in voltage-gated ion channels) for capsaicin and other activators to the left.…”