No 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...

BackgroundLow 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.ResultsRecombinant 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.ConclusionsThe 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.

Buprenorphine is a potent local anesthetic and blocks voltage-gated Na(+) channels via the local anesthetic binding site. This property is likely to be relevant when buprenorphine is used for pain treatment and for local anesthesia.

Our results confirm the clinical experience that desflurane is more irritating than isoflurane at equal anesthetic gas concentration, whereas sevoflurane does not activate tracheobronchial sensory nerves to release neuropeptides and induce neurogenic inflammation. Both irritant receptor channels, TRPA1 more than TRPV1, are involved in mediating the adverse effects that may even extend to systemic proinflammatory sequelae.