Abstract
Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca2+ channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Cav2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E (calcium channel, voltage-dependent, R type, alpha 1E subunit) gene that encodes Cav2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity.
Highlights
Voltage-activated Ca2+ channels (VACCs) mediate Ca2+ entry into cells in response to membrane depolarization and play a crucial role in the nervous system by controlling membrane excitability and calcium signaling [1]
To identify the linkage disequilibrium (LD) blocks in the approximately 640 kbp region that contains the CACNA1E gene, 223 single-nucleotide polymorphisms (SNPs) among 1,199,187 markers included in the whole-genome genotyping (Human 1M-Duo v3 Bead Chip) were tested using genomic samples from 100 Japanese patients (Fig. S1)
A total of 13 LD blocks, LD1-13, were observed within and around the CACNA1E gene region, and 42 Tag SNPs were selected in this region (Table 1)
Summary
Voltage-activated Ca2+ channels (VACCs) mediate Ca2+ entry into cells in response to membrane depolarization and play a crucial role in the nervous system by controlling membrane excitability and calcium signaling [1]. VACCs are composed of a major pore-forming subunit (a1A-I and a1S) and multiple auxiliary subunits (a2-d, b, and c). Molecular characterizations have determined that the a1E subunit encodes Cav2.3 (R-type) VACCs [2,3]. Cav2.3 VACCs are reported to be distributed throughout the central and peripheral nervous systems, including pain pathways [4,5]. Cav2.3 knockout mice have been reported to show functional deficits in pain perception [6]. Cav2.3 VACCs may be hypothesized to contribute to pain transmission
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