title: Altered pain responses in mice lacking alpha 1E subunit of the voltage-dependent Ca2+ channel.
abstract: alpha(1) subunit of the voltage-dependent Ca(2+) channel is essential for channel function and determines the functional specificity of various channel types. alpha(1E) subunit was originally identified as a neuron-specific one, but the physiological function of the Ca(2+) channel containing this subunit (alpha(1E) Ca(2+) channel) was not clear compared with other types of Ca(2+) channels because of the limited availability of specific blockers. To clarify the physiological roles of the alpha(1E) Ca(2+) channel, we have generated alpha(1E) mutant (alpha(1E)-/-) mice by gene targeting. The lacZ gene was inserted in-frame and used as a marker for alpha(1E) subunit expression. alpha(1E)-/- mice showed reduced spontaneous locomotor activities and signs of timidness, but other general behaviors were apparently normal. As involvement of alpha(1E) in pain transmission was suggested by localization analyses with 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside staining, we conducted several pain-related behavioral tests using the mutant mice. Although alpha(1E)+/- and alpha(1E)-/- mice exhibited normal pain behaviors against acute mechanical, thermal, and chemical stimuli, they both showed reduced responses to somatic inflammatory pain. alpha(1E)+/- mice showed reduced response to visceral inflammatory pain, whereas alpha(1E)-/- mice showed apparently normal response compared with that of wild-type mice. Furthermore, alpha(1E)-/- mice that had been presensitized with a visceral noxious conditioning stimulus showed increased responses to a somatic inflammatory pain, in marked contrast with the wild-type mice in which long-lasting effects of descending antinociceptive pathway were predominant. These results suggest that the alpha(1E) Ca(2 +) channel controls pain behaviors by both spinal and supraspinal mechanisms.
authors.affiliation: Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, and CREST, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Saegusa
authors.forename: T
authors.initials: T
authors.lastname: Kurihara
authors.forename: S
authors.initials: S
authors.lastname: Zong
authors.forename: O
authors.initials: O
authors.lastname: Minowa
authors.forename: A
authors.initials: A
authors.lastname: Kazuno
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuda
authors.forename: H
authors.initials: H
authors.lastname: Yamanaka
authors.forename: M
authors.initials: M
authors.lastname: Osanai
authors.forename: T
authors.initials: T
authors.lastname: Noda
authors.forename: T
authors.initials: T
authors.lastname: Tanabe
mesh_terms: D019342:Acetic Acid / Q000633:toxicity; D000818:Animals; D001007:Anxiety / Q000235:genetics; D002118:Calcium / Q000502:physiology*; D020908:Calcium Channels, R-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005106:Exploratory Behavior; D005239:Fear; D005557:Formaldehyde / Q000633:toxicity; D015870:Gene Expression; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D017136:Ion Transport; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000503:physiopathology; D010146:Pain / Q000503:physiopathology*; D000699:Pain Insensitivity, Congenital / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D010147:Pain Measurement; D010538:Peritonitis / Q000139:chemically induced / Q000503:physiopathology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013216:Reflex, Startle / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020908:Calcium Channels, R-Type; D011993:Recombinant Fusion Proteins; D005557:Formaldehyde; D019342:Acetic Acid; D002118:Calcium