Altered pain responses in mice lacking α 1E subunit of the voltage-dependent Ca 2+ channel

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Abstract
α1 subunit of the voltage-dependent Ca2+ channel is essential for channel function and determines the functional specificity of various channel types. α1E subunit was originally identified as a neuron-specific one, but the physiological function of the Ca2+ channel containing this subunit (α1E Ca2+ channel) was not clear compared with other types of Ca2+ channels because of the limited availability of specific blockers. To clarify the physiological roles of the α1E Ca2+ channel, we have generated α1E mutant (α1E−/−) mice by gene targeting. The lacZ gene was inserted in-frame and used as a marker for α1E subunit expression. α1E−/− mice showed reduced spontaneous locomotor activities and signs of timidness, but other general behaviors were apparently normal. As involvement of α1E in pain transmission was suggested by localization analyses with 5-bromo-4-chloro-3-indolyl β-d-galactopyranoside staining, we conducted several pain-related behavioral tests using the mutant mice. Although α1E+/− and α1E−/− mice exhibited normal pain behaviors against acute mechanical, thermal, and chemical stimuli, they both showed reduced responses to somatic inflammatory pain. α1E+/− mice showed reduced response to visceral inflammatory pain, whereas α1E−/− mice showed apparently normal response compared with that of wild-type mice. Furthermore, α1E−/− 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 α1E Ca2 + channel controls pain behaviors by both spinal and supraspinal mechanisms.