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.
References
[1]
Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16: 521–555.
[2]
Zhang JF, Randall AD, Ellinor PT, Horne WA, Sather WA, et al. (1993) Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons. Neuropharmacology 32: 1075–1088.
[3]
Yokoyama CT, Westenbroek RE, Hell JW, Soong TW, Snutch TP, et al. (1995) Biochemical properties and subcellular distribution of the neuronal class E calcium channel α1 subunit. J Neurosci 15: 6419–6432.
[4]
Westenbroek RE, Hoskins L, Catterall WA (1998) Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals. J Neurosci 18: 6319–6330.
[5]
Murakami M, Nakagawasai O, Suzuki T, Mobarakeh, II, Sakurada Y, et al. (2004) Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel α1 subunits in the dorsal horn of spinal cord in mice. Brain Res 1024: 122–129.
[6]
Saegusa H, Kurihara T, Zong S, Minowa O, Kazuno A, et al. (2000) Altered pain responses in mice lacking α1E subunit of the voltage-dependent Ca2+ channel. Proc Natl Acad Sci U S A 97: 6132–6137.
[7]
Ikeda K, Ide S, Han W, Hayashida M, Uhl GR, et al. (2005) How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 26: 311–317.
[8]
Coulbault L, Beaussier M, Verstuyft C, Weickmans H, Dubert L, et al. (2006) Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther 79: 316–324.
[9]
Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, et al. (1998) μ Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res 54: 321–326.
[10]
Sora I, Elmer G, Funada M, Pieper J, Li XF, et al. (2001) μ Opiate receptor gene dose effects on different morphine actions: evidence for differential in vivo μ receptor reserve. Neuropsychopharmacology 25: 41–54.
[11]
Sora I, Takahashi N, Funada M, Ujike H, Revay RS, et al. (1997) Opiate receptor knockout mice define μ receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci U S A 94: 1544–1549.
[12]
Kasai S, Ikeda K (2011) Pharmacogenomics of the human μ-opioid receptor. Pharmacogenomics 12: 1305–1320.
[13]
Dogrul A, Zagli U, Tulunay FC (2002) The role of T-type calcium channels in morphine analgesia, development of antinociceptive tolerance and dependence to morphine, and morphine abstinence syndrome. Life Sci 71: 725–734.
[14]
Contreras E, Tamayo L, Amigo M (1988) Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance. Eur J Pharmacol 148: 463–466.
[15]
Michaluk J, Karolewicz B, Antkiewicz-Michaluk L, Vetulani J (1998) Effects of various Ca2+ channel antagonists on morphine analgesia, tolerance and dependence, and on blood pressure in the rat. Eur J Pharmacol 352: 189–197.
Holmkvist J, Tojjar D, Almgren P, Lyssenko V, Lindgren CM, et al. (2007) Polymorphisms in the gene encoding the voltage-dependent Ca2+ channel Cav2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion. Diabetologia 50: 2467–2475.
[18]
Muller YL, Hanson RL, Zimmerman C, Harper I, Sutherland J, et al. (2007) Variants in the Cav2.3 (α1E) subunit of voltage-activated Ca2+ channels are associated with insulin resistance and type 2 diabetes in Pima Indians. Diabetes 56: 3089–3094.
[19]
Fukuda K, Hayashida M, Ide S, Saita N, Kokita Y, et al. (2009) Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery. Pain 147: 194–201.
[20]
Bisgaard T, Klarskov B, Rosenberg J, Kehlet H (2001) Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 90: 261–269.
[21]
Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, et al. (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74: 106–120.
[22]
Carlson CS, Eberle MA, Rieder MJ, Smith JD, Kruglyak L, et al. (2003) Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet 33: 518–521.
[23]
de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, et al. (2005) Efficiency and power in genetic association studies. Nat Genet 37: 1217–1223.
[24]
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
[25]
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. (2002) The structure of haplotype blocks in the human genome. Science 296: 2225–2229.
[26]
Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39: 175–191.
[27]
Angst MS, Phillips NG, Drover DR, Tingle M, Ray A, et al. (2012) Pain sensitivity and opioid analgesia: a pharmacogenomic twin study. Pain 153: 1397–1409.
[28]
Perret D, Luo ZD (2009) Targeting voltage-gated calcium channels for neuropathic pain management. Neurotherapeutics 6: 679–692.
[29]
Park J, Luo ZD (2010) Calcium channel functions in pain processing. Channels (Austin) 4: 510–517.
[30]
Newcomb R, Szoke B, Palma A, Wang G, Chen X, et al. (1998) Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas. Biochemistry 37: 15353–15362.
[31]
Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, et al. (2000) Nomenclature of voltage-gated calcium channels. Neuron 25: 533–535.
[32]
Marubio LM, Roenfeld M, Dasgupta S, Miller RJ, Philipson LH (1996) Isoform expression of the voltage-dependent calcium channel α1E. Receptors Channels 4: 243–251.
[33]
Pereverzev A, Leroy J, Krieger A, Malecot CO, Hescheler J, et al. (2002) Alternate splicing in the cytosolic II–III loop and the carboxy terminus of human E-type voltage-gated Ca2+ channels: electrophysiological characterization of isoforms. Mol Cell Neurosci 21: 352–365.