The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors

Abstract

Anesthetic agents can induce a paradox activation and sensitization of nociceptive sensory neurons and, thus, potentially facilitate pain processing. Here we identify distinct molecular mechanisms that mediate an activation of sensory neurons by 2,6-diisopropylphenol (propofol), a commonly used intravenous anesthetic known to elicit intense pain upon injection. Clinically relevant concentrations of propofol activated the recombinant transient receptor potential (TRP) receptors TRPA1 and TRPV1 heterologously expressed in HEK293t cells. In dorsal root ganglion (DRG) neurons, propofol-induced activation correlated better to expression of TRPA1 than of TRPV1. However, pretreatment with the protein kinase C activator 4␤-phorbol 12-myristate 13-acetate (PMA) resulted in a significantly sensitized propofol-induced activation of TRPV1 in DRG neurons as well as in HEK293t cells. Pharmacological and genetic silencing of both TRPA1 and TRPV1 only partially abrogated propofol-induced responses in DRG neurons. The remaining propofol-induced activation was abolished by the selective ␥-aminobutyric acid, type A (GABA A ) receptor antagonist picrotoxin. Propofol but not GABA evokes a release of calcitonin generelated peptide, a key component of neurogenic inflammation, from isolated peripheral nerves of wild-type but not TRPV1 and TRPA1-deficient mice. Moreover, propofol but not GABA induced an intense pain upon intracutaneous injection. As both the release of calcitonin gene-related peptide and injection pain by propofol seem to be independent of GABA A receptors, our data identify TRPV1 and TRPA1 as key molecules for propofol-induced excitation of sensory neurons. This study warrants further investigations into the role of anesthetics to induce nociceptor sensitization and to foster postoperative pain.The intravenous general anesthetic propofol 3 (2,6-diisopropylphenol) has become one of the most widely used anesthetics.Due to a short context-sensitive half-time, propofol is used for sedations as well as for total intravenous anesthesia during surgery. A drawback of propofol, however, is its high potential to induce intense burning pain upon injection. Depending on the concentration (0.5-2%), the galenic formulation, and co-medication, 24 -90% of all patients receiving propofol experience injection pain (1). It was hypothesized that propofol might indirectly or directly interact with sensory nerve fibers located in the venous adventitia (2-4). A recent study claims that the irritant receptor TRPA1, which is expressed in nociceptive sensory neurons, is the predominant molecular entity mediating activation of peripheral nerve endings by general anesthetics (5). Also, TRPA1 was found to mediate propofol-induced pain behavior induced by intranasal propofol and flexor reflex response upon intra-arterial propofol (5). TRPA1 is an excitatory cation channel that is activated by pungent or irritating substances such as acrolein, mustard oil, and formalin (6). TRPA1 has also been demonstrated to be involved in the development of increa...

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…This assumption has suffered a first major setback when mice with a targeted deletion of the heatactivated ion channel and capsaicin receptor TRPV1 (transient receptor potential vanniloid type 1) showed the expected loss of heat-activated current in capsaicin-sensitive dorsal root ganglion (DRG) neurons but almost normal nocifensive behavior and completely normal primary afferent discharge in response to moderate noxious heat (90,777,803). Another example is the functional expression of GABA A receptor channels in all DRG neurons as opposed to their lack in peripheral nerve axons and terminals (199). Thus selective trafficking, variable heteromerization, posttranslational modifications of proteins may create relevant differences between the cellular model and the real nerve endings.…”

Propacetamol-Induced Injection Pain Is Associated with Activation of Transient Receptor Potential Vanilloid 1 Channels

“…Injection pain as a result of activation of TRP channels has been shown for propofol (Fischer et al, 2010), etomidate (Matta et al, 2008), and lidocaine as well as for other local anesthetics (Leffler et al, 2008(Leffler et al, , 2011. Although TRPA1 is the channel that seems to be predominantly activated by etomidate and propofol (Matta et al, 2008), the latter at least also activates TRPV1 after receptor sensitization in mouse dorsal root ganglion neurons (Fischer et al, 2010).…”

“…Although TRPA1 is the channel that seems to be predominantly activated by etomidate and propofol (Matta et al, 2008), the latter at least also activates TRPV1 after receptor sensitization in mouse dorsal root ganglion neurons (Fischer et al, 2010). Local anesthetics activate TRPV1, and lidocaine induces a strong sensitization to heat and capsaicin.…”

TRPV1 Antagonists as Analgesic Agents

“…Thus, TRPV1 functions as a molecular integrator of painful stimuli in which each stimulus sensitizes the channel to other stimuli, with the end-result that TRPV1 acts as a molecular amplifier in the sensory neuron [55]. Interestingly, TRPV1 (perhaps together with TRPA1) is also responsible for the paradox painful action of the commonly used general anaesthetic drug propofol [56].…”