title: 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 4β-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 γ-aminobutyric acid, type A (GABA(A)) receptor antagonist picrotoxin. Propofol but not GABA evokes a release of calcitonin gene-related 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.
authors.affiliation: Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Michael J M
authors.initials: MJ
authors.lastname: Fischer
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.forename: Florian
authors.initials: F
authors.lastname: Niedermirtl
authors.forename: Katrin
authors.initials: K
authors.lastname: Kistner
authors.forename: Mirjam
authors.initials: M
authors.lastname: Eberhardt
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.forename: Carla
authors.initials: C
authors.lastname: Nau
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D010852:Picrotoxin / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D011963:Receptors, GABA-A; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D050051:Transient Receptor Potential Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018686:Anesthetics, Intravenous; D015740:Calcitonin Gene-Related Peptide; D018756:GABA Antagonists; D010852:Picrotoxin; D015742:Propofol; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C494482:TRPV1 protein, human; C475685:Trpa1 protein, mouse
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