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)....

No abstract

No abstract

Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5′-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean±SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45±9.27 mg, 10.84±2.24 mg, and 13.07±2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

No abstract

No abstract

Ethanol is considered to activate the brain reward system by increasing the release of an endogenous opioid receptor ligand, β-endorphin. The polymorphism A118G in the µ-opioid receptor gene (OPRM1) causes the amino acid change Asn40Asp and has been reported to affect the affinity of the ligand for the receptor. The association of this polymorphism with the vulnerability to alcohol dependence has been studied in many populations, but not yet in Japanese people. In the present study, we compared the frequencies of the polymorphism OPRM1 A118G between patients with alcohol dependence and healthy control subjects living in a Japanese provincial prefecture. We also genotyped a polymorphism, G1510A, in the acetaldehyde dehydrogenase 2 gene (ALDH2), in which the A allele causes poor metabolism of acetaldehyde, a major metabolite of alcohol. Both OPRM1 118G and ALDH2 1510G were significantly associated with alcohol dependence. These results suggest that OPRM1 118G in addition to ALDH2 1510G might be one of the risk factors for alcohol dependence in Japanese people.