Opposite Associations Between the rs3845446 Single-Nucleotide Polymorphism of the CACNA1E Gene and Postoperative Pain-Related Phenotypes in Gastrointestinal Surgery Versus Previously Reported Orthognathic Surgery


      • Pain-related phenotypes (PP; analgesic requirements or pain scores) were examined.
      • The rs3845446 single nucleotide polymorphism (SNP) was genotyped in the subjects.
      • The G allele of the rs3845446 SNP enhanced PP after gastrointestinal surgery (GS).
      • Association of the SNP with PP after GS opposed to that after orthognathic surgery.
      • Cav2.3 channel functions might differentiate PP after GS and orthognathic surgery.


      Cav2.3 (R-type) voltage-activated Ca2+ channels (VACCs), encoded by the calcium channel, voltage-dependent, R-type, α1E subunit (CACNA1E) gene, are responsible for transmission of somatic inflammatory pain, and activation of antinociception elicited by visceral inflammatory pain stimuli. Carriers of the minor G allele of the rs3845446 single-nucleotide polymorphism (SNP) of the CACNA1E gene reportedly exhibit a decrease in opioid requirements to control typical somatic inflammatory pain after orthognathic surgery (ie, a painful cosmetic surgery), suggesting the downregulation of Cav2.3 VACC function that is responsible for transmission of somatic inflammatory pain in these carriers. Gastrointestinal surgery involves somatic and visceral inflammatory pain, in which visceral inflammatory pain stimuli activate Cav2.3 VACC-mediated antinociception. Unknown is whether pain-related phenotypes after gastrointestinal surgery are affected in these carriers. The present study used a correlational design to examine the effect of the rs3845446 SNP on postoperative pain-related phenotypes in 2 groups of patients who underwent gastrointestinal surgery. Carriers of the minor G allele had greater opioid requirements after laparoscopic colectomy when intravenous patient-controlled analgesia was used, and reported higher pain scores after open gastrointestinal surgery when postoperative analgesia was managed with continuous epidural analgesia and rescue analgesics. These results suggest that pain-related phenotypes after gastrointestinal surgery are enhanced in carriers of the minor G allele of the rs3845446 SNP, possibly through impairment of Cav2.3 VACC function that is responsible for the activation of visceral inflammatory pain stimulus-elicited antinociception.


      Carriers of the minor allele of the rs3845446 SNP of the CACNA1E gene required more opioid or reported higher pain scores after gastrointestinal surgery, and required less opioid after orthognathic surgery. The difference may result from the presence of visceral inflammatory pain stimulus that activates Cav2.3 VACCs-mediated antinociception.

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        • Aoki Y.
        • Yoshida K.
        • Nishizawa D.
        • Kasai S.
        • Ichinohe T.
        • Ikeda K.
        • Fukuda K.
        Factors that affect intravenous patient-controlled analgesia for postoperative pain following orthognathic surgery for mandibular prognathism.
        PLoS One. 2014; 9: e98548
        • Barbanti P.
        • Grazzi L.
        • Egeo G.
        • Padovan A.M.
        • Liebler E.
        • Bussone G.
        Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: An open-label study.
        J Headache Pain. 2015; 16: 61
        • Beal M.C.
        Viscerosomatic reflexes: A review.
        J Am Osteopath Assoc. 1985; 85: 786-801
        • Bian X.
        • Zhou X.
        • Galligan J.J.
        R-type calcium channels in myenteric neurons of guinea pig small intestine.
        Am J Physiol Gastrointest Liver Physiol. 2004; 287: G134-G142
        • Blichfeldt-Eckhardt M.R.
        • Ording H.
        • Andersen C.
        • Licht P.B.
        • Toft P.
        Early visceral pain predicts chronic pain after laparoscopic cholecystectomy.
        Pain. 2014; 155: 2400-2407
        • Bohotin C.
        • Scholsem M.
        • Bohotin V.
        • Franzen R.
        • Schoenen J.
        Vagus nerve stimulation attenuates heat- and formalin-induced pain in rats.
        Neurosci Lett. 2003; 351: 79-82
        • Bouhassira D.
        • Chollet R.
        • Coffin B.
        • Lémann M.
        • Le Bars D.
        • Willer J.C.
        • Jian R.
        Inhibition of a somatic nociceptive reflex by gastric distention in humans.
        Gastroenterology. 1994; 107: 985-992
        • Bouhassira D.
        • Sabaté J.M.
        • Coffin B.
        • Le Bars D.
        • Willer J.C.
        • Jian R.
        Effects of rectal distensions on nociceptive flexion reflexes in humans.
        Am J Physiol. 1998; 275: G410-G417
        • Buhagiar L.
        • Cassar O.A.
        • Brincat M.P.
        • Buttigieg G.G.
        • Inglott A.S.
        • Adami M.Z.
        • Azzopardi L.M.
        Predictors of post-caesarean section pain and analgesic consumption.
        J Anaesthesiol Clin Pharmacol. 2011; 27: 185-191
        • Buhagiar L.M.
        • Cassar O.A.
        • Brincat M.P.
        • Buttigieg G.G.
        • Inglott A.S.
        • Adami M.Z.
        • Azzopardi L.M.
        Pre-operative pain sensitivity: A prediction of post-operative outcome in the obstetric population.
        J Anaesthesiol Clin Pharmacol. 2013; 29: 465-471
        • Busch V.
        • Zeman F.
        • Heckel A.
        • Menne F.
        • Ellrich J.
        • Eichhammer P.
        The effect of transcutaneous vagus nerve stimulation on pain perception: An experimental study.
        Brain Stimul. 2013; 6: 202-209
        • Cervero F.
        Sensory innervation of the viscera: Peripheral basis of visceral pain.
        Physiol Rev. 1994; 74: 95-138
        • De Proost I.
        • Brouns I.
        • Pintelon I.
        • Timmermans J.P.
        • Adriaensen D.
        Pulmonary expression of voltage-gated calcium channels: Special reference to sensory airway receptors.
        Histochem Cell Biol. 2007; 128: 301-316
        • Gebhart G.F.
        Visceral pain-peripheral sensitization.
        Gut. 2000; 47 (discussion: iv58): iv54-iv55
        • Hayashida M.
        • Nagashima M.
        • Satoh Y.
        • Katoh R.
        • Tagami M.
        • Ide S.
        • Kasai S.
        • Nishizawa D.
        • Ogai Y.
        • Hasegawa J.
        • Komatsu H.
        • Sora I.
        • Fukuda K.
        • Koga H.
        • Hanaoka K.
        • Ikeda K.
        Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype.
        Pharmacogenomics. 2008; 9: 1605-1616
        • Ide S.
        • Nishizawa D.
        • Fukuda K.
        • Kasai S.
        • Hasegawa J.
        • Hayashida M.
        • Minami M.
        • Ikeda K.
        Association between genetic polymorphisms in Cav2.3 (R-type) Ca2+ channels and fentanyl sensitivity in patients undergoing painful cosmetic surgery.
        PLoS One. 2013; 8: e70694
        • Ishiguro M.
        • Wellman T.L.
        • Honda A.
        • Russell S.R.
        • Tranmer B.I.
        • Wellman G.C.
        Emergence of a R-type Ca2+ channel (CaV 2.3) contributes to cerebral artery constriction after subarachnoid hemorrhage.
        Circ Res. 2005; 96: 419-426
        • Jänig W.
        • Khasar S.G.
        • Levine J.D.
        • Miao F.J.
        The role of vagal visceral afferents in the control of nociception.
        Prog Brain Res. 2000; 122: 273-287
        • Joris J.
        • Thiry E.
        • Paris P.
        • Weerts J.
        • Lamy M.
        Pain after laparoscopic cholecystectomy: Characteristics and effect of intraperitoneal bupivacaine.
        Anesth Analg. 1995; 81: 379-384
        • Kim S.H.
        • Stoicea N.
        • Soghomonyan S.
        • Bergese S.D.
        Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: Systematic review.
        Front Pharmacol. 2014; 5: 108
        • Kirchner A.
        • Birklein F.
        • Stefan H.
        • Handwerker H.O.
        Left vagus nerve stimulation suppresses experimentally induced pain.
        Neurology. 2000; 55: 1167-1171
        • Kirchner A.
        • Stefan H.
        • Bastian K.
        • Birklein F.
        Vagus nerve stimulation suppresses pain but has limited effects on neurogenic inflammation in humans.
        Eur J Pain. 2006; 10: 449-455
        • Kurihara T.
        • Nonaka T.
        • Tanabe T.
        Acetic acid conditioning stimulus induces long-lasting antinociception of somatic inflammatory pain.
        Pharmacol Biochem Behav. 2003; 74: 841-849
        • Laqua R.
        • Leutzow B.
        • Wendt M.
        • Usichenko T.
        Transcutaneous vagal nerve stimulation may elicit anti- and pro-nociceptive effects under experimentally-induced pain: A crossover placebo-controlled investigation.
        Auton Neurosci. 2014; 185: 120-122
        • Lyons P.J.
        • Rivosecchi R.M.
        • Nery J.P.
        • Kane-Gill S.L.
        Fentanyl-induced hyperalgesia in acute pain management.
        J Pain Palliat Care Pharmacother. 2015; 29: 153-160
        • Mieda T.
        • Nishizawa D.
        • Nakagawa H.
        • Tsujita M.
        • Imanishi H.
        • Terao K.
        • Yoshikawa H.
        • Itoh K.
        • Amano K.
        • Tashiro J.
        • Ishii T.
        • Ariyama J.
        • Yamaguchi S.
        • Kasai S.
        • Hasegawa J.
        • Ikeda K.
        • Kitamura A.
        • Hayashida M.
        Genome-wide association study identifies candidate loci associated with postoperative fentanyl requirements after laparoscopic-assisted colectomy.
        Pharmacogenomics. 2016; 17: 133-145
        • Mo A.
        • Mukamel E.A.
        • Davis F.P.
        • Luo C.
        • Henry G.L.
        • Picard S.
        • Urich M.A.
        • Nery J.R.
        • Sejnowski T.J.
        • Lister R.
        • Eddy S.R.
        • Ecker J.R.
        • Nathans J.
        Epigenomic signatures of neuronal diversity in the mammalian brain.
        Neuron. 2015; 86: 1369-1384
        • Napadow V.
        • Edwards R.R.
        • Cahalan C.M.
        • Mensing G.
        • Greenbaum S.
        • Valovska A.
        • Li A.
        • Kim J.
        • Maeda Y.
        • Park K.
        • Wasan A.D.
        Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation.
        Pain Med. 2012; 13: 777-789
      1. National Center for Biotechnology Information: dbSNP: Available at: Accessed July 17, 2016

        • Nesbitt A.D.
        • Marin J.C.
        • Tompkins E.
        • Ruttledge M.H.
        • Goadsby P.J.
        Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment.
        Neurology. 2015; 84: 1249-1253
        • Ness T.J.
        • Gebhart G.F.
        Interactions between visceral and cutaneous nociception in the rat: I. Noxious cutaneous stimuli inhibit visceral nociceptive neurons and reflexes.
        J Neurophysiol. 1991; 66: 20-28
        • Ness T.J.
        • Gebhart G.F.
        Interactions between visceral and cutaneous nociception in the rat: II. Noxious visceral stimuli inhibit cutaneous nociceptive neurons and reflexes.
        J Neurophysiol. 1991; 66: 29-39
        • Randich A.
        • Gebhart G.F.
        Vagal afferent modulation of nociception.
        Brain Res Rev. 1992; 17: 77-99
        • Rivosecchi R.M.
        • Rice M.J.
        • Smithburger P.L.
        • Buckley M.S.
        • Coons J.C.
        • Kane-Gill S.L.
        An evidence based systematic review of remifentanil associated opioid-induced hyperalgesia.
        Expert Opin Drug Saf. 2014; 13: 587-603
        • Saegusa H.
        • Kurihara T.
        • Zong S.
        • Minowa O.
        • Kazuno A.
        • Han W.
        • Matsuda Y.
        • Yamanaka H.
        • Osanai M.
        • Noda T.
        • Tanabe T.
        Altered pain responses in mice lacking α1E subunit of the voltage-dependent Ca2+ channel.
        Proc Natl Acad Sci U S A. 2000; 97: 6132-6137
        • Sikandar S.
        • Dickenson A.H.
        Visceral pain: The ins and outs, the ups and downs.
        Curr Opin Support Palliat Care. 2012; 6: 17-26
        • Straube A.
        • Ellrich J.
        • Eren O.
        • Blum B.
        • Ruscheweyh R.
        Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): A randomized, monocentric clinical trial.
        J Headache Pain. 2015; 16: 543
        • Thurston C.L.
        • Randich A.
        Quantitative characterization and spinal substrates of antinociception produced by electrical stimulation of the subdiaphragmatic vagus in rats.
        Pain. 1991; 44: 201-209
        • Ure B.M.
        • Troidl H.
        • Spangenberger W.
        • Dietrich A.
        • Lefering R.
        • Neugebauer E.
        Pain after laparoscopic cholecystectomy: Intensity and localization of pain and analysis of predictors in preoperative symptoms and intraoperative events.
        Surg Endosc. 1994; 8: 90-96
        • Zurowski D.
        • Nowak Ł.
        • Wordliczek J.
        • Dobrogowski J.
        • Thor P.J.
        Effects of vagus nerve stimulation in visceral pain model.
        Folia Med Cracov. 2012; 52: 57-69