The importance of voltage-dependent Ca2+ channels (VDCCs) in pain transmission has been noticed gradually, as several VDCC blockers have been shown to be effective in inhibiting this process. In particular, the N-type VDCC has attracted attention, because inhibitors of this channel are effective in various aspects of pain-related phenomena. To understand the genuine contribution of the N-type VDCC to the pain transmission system, we generated mice deficient in this channel by gene targeting. We report here that mice lacking N-type VDCCs show suppressed responses to a painful stimulus that induces inflammation and show markedly reduced symptoms of neuropathic pain, which is caused by nerve injury and is known to be difficult to treat by currently available therapeutic methods. This finding clearly demonstrates that the N-type VDCC is essential for development of neuropathic pain and, therefore, controlling the activity of this channel can be of great importance for the management of neuropathic pain.

␣1 subunit of the voltage-dependent Ca 2؉ channel is essential for channel function and determines the functional specificity of various channel types. ␣1E subunit was originally identified as a neuron-specific one, but the physiological function of the Ca 2؉ channel containing this subunit (␣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 ␣1E Ca 2؉ channel, we have generated ␣1E mutant (␣1E؊͞؊) mice by gene targeting. The lacZ gene was inserted in-frame and used as a marker for ␣1E subunit expression. ␣1E؊͞؊ mice showed reduced spontaneous locomotor activities and signs of timidness, but other general behaviors were apparently normal. As involvement of ␣1E in pain transmission was suggested by localization analyses with 5-bromo-4-chloro-3-indolyl ␤-D-galactopyranoside staining, we conducted several pain-related behavioral tests using the mutant mice. Although ␣1E؉͞؊ and ␣1E؊͞؊ mice exhibited normal pain behaviors against acute mechanical, thermal, and chemical stimuli, they both showed reduced responses to somatic inflammatory pain. ␣1E؉͞؊ mice showed reduced response to visceral inflammatory pain, whereas ␣1E؊͞؊ mice showed apparently normal response compared with that of wild-type mice. Furthermore, ␣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 ␣1E Ca 2 ؉ channel controls pain behaviors by both spinal and supraspinal mechanisms.V oltage-dependent calcium channels (VDCCs) are classified into several distinct groups termed L-, N-, P-, Q-, R-, and T-types (1, 2). These types of VDCCs play important roles in various neuronal activities, including the control of neurotransmitter release, membrane excitability, and gene expression (3), but exact roles of each channel type are not necessarily clarified. In particular, functions of the R-type Ca 2ϩ channel are least understood. The R-type Ca 2ϩ channel was originally defined as a channel ''Resistant'' to blockers for L-, N-, P-, and Q-type Ca 2ϩ channels (4); therefore, it is possible that the R-type current is a mixture of several different drug-resistant Ca 2ϩ currents. Although the R-type Ca 2ϩ channel is suggested to play a critical role in the release of neurotransmitters and somatodendritic excitability in a certain set of neurons (4-6), the physiological functions of this channel remain to be clarified.VDCCs are heteromultimers composed of ␣ 1 , ␣ 2 -␦, ␤, and ␥ subunits. ␣ 1 subunit is essential for channel function and determines the type of each Ca 2ϩ channel. So far, 10 different ␣ 1 cDNAs (␣ 1A-I and ␣ 1S ) have been cloned from a variety of tissues, and extensive studies have been made to clarify the relationship between each cloned ␣ 1 subunit and native Ca 2ϩ channels (2)....

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