title: Propofol-induced pain sensation involves multiple mechanisms in sensory neurons.
abstract: Propofol, a commonly used intravenous anesthetic agent, is known to at times cause pain sensation upon injection in humans. However, the molecular mechanisms underlying this effect are not fully understood. Although propofol was reported to activate human transient receptor potential ankyrin 1 (TRPA1) in this regard, its action on human TRP vanilloid 1 (TRPV1), another nociceptive receptor, is unknown. Furthermore, whether propofol activates TRPV1 in rodents is controversial. Here, we show that propofol activates human and mouse TRPA1. In contrast, we did not observe propofol-evoked human TRPV1 activation, while the ability of propofol to activate mouse TRPV1 was very small. We also found that propofol caused increases in intracellular Ca(2+) concentrations in a considerable portion of dorsal root ganglion (DRG) cells from mice lacking both TRPV1 and TRPA1, indicating the existence of TRPV1- and TRPA1-independent mechanisms for propofol action. In addition, propofol produced action potential generation in a type A γ-amino butyric acid (GABAA) receptor-dependent manner. Finally, we found that both T-type and L-type Ca(2+) channels are activated downstream of GABAA receptor activation by propofol. Thus, we conclude that propofol may cause pain sensation through multiple mechanisms involving not only TRPV1 and TRPA1 but also voltage-gated channels downstream of GABAA receptor activation.
authors.affiliation: Department of Physiological Sciences, the Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi, 444-8585, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Nishimoto
authors.forename: Makiko
authors.initials: M
authors.lastname: Kashio
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018686:Anesthetics, Intravenous / Q000009:adverse effects*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000009:adverse effects*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018686:Anesthetics, Intravenous; D015220:Calcium Channels; D011963:Receptors, GABA-A; D015742:Propofol