Overcoming refractory pain : prevention of tolerance of pain by simultaneous activation of G_<i/o>-coupled receptors

2011 Fiscal Year Final Research Report

• Project/Area Number: 21600009
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 疼痛学
• Research Institution: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• Principal Investigator: UEZONO Yasuhito 独立行政法人国立がん研究センター, 研究所, 分野長 (20213340)
• Project Period (FY): 2009 – 2011
• Keywords: GABA_B受容体 / μ受容体 / 耐性 / オピオイド / FRET / β-アレスチン / ケタミン / 受容体陥入

Research Abstract

Management of refractory pain seen in advanced cancer patients is hard to control, and in such cases intrathecal morphine(ITM) or intrathecal baclofen treatment(ITB) is currently used. However, persistent use of either ITM or ITB often causes tolerance due to desensitization ofμ-opioid(μOR) or GABA_B receptors(GBR).
To overcome such issue, we demonstrated by using in vitro experimental system that 1) treatment of baclofen with ketamine suppressed GBR desensitization, 2) GBR did not internalize because of failure of association withβ-arrestins, key proteins for receptor desensitization, 3) in cells coexpressingμOR and GBR, combination of low concentrations of morphine and baclofen hardly caused receptor desensitization. These results suggest that some of newer treatments described above would be useful for the control of refractory pain by prevention of receptor desensitization.

Research Products

• [Journal Article] GABA_B receptors do not internalize after baclofen treatment possibly due to lack of theβ-arrestin association ; a real-time visualization study (2012)
  • Author(s): Sudo, Y., Hojo, M., Ando, Y., Takada, M., Murata, H., Kurata, S., Kanaide, M., Nishida, N., Uezono, Y.
  • Journal Title: Synapse, Epub ahead of print
  • DOI: DOI:10.1002/syn.21565
  • Peer Reviewed
• [Journal Article] Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival (2011)
  • Author(s): Fujitsuka, N., Asakawa, A., Uezono, Y., Minami, K., Yamaguchi, T., Niijima, A., Yada, T., Maejima, Y., Sedbazar, U., Sakai, T., Hattori, T., Kase, Y., Inui, A.
  • Journal Title: Transl Psychiatr Volume: 1 Pages: 23
  • DOI: DOI:10.1038/tp.2011.25
  • Peer Reviewed
• [Journal Article] Possible involvement of prolonging spinalμ-opioid receptor desensitization in the development of antihyperalgesic tolerance toμ-opioids under a neuropathic pain-like state (2011)
  • Author(s): Narita, M., Imai, S., Nakamura, A., Ozeki, A., Asato, M., Rahmadi, M., Sudo, Y., Hojo, M., Uezono, Y., Devi, L. A., Kuzumaki, N., Suzuki, T.
  • Journal Title: Addict Biol
  • DOI: DOI:10.1111/j.1369-1600.2011.00354.x
  • Peer Reviewed
• [Journal Article] がん患者の症状緩和に役立つ漢方薬-漢方薬の有効性を示す、臨床につながる基礎研究- (2011)
  • Author(s): 上園保仁
  • Journal Title: がん患者と対症療法 Volume: 22(2) Pages: 140-146
• [Journal Article] 腸管神経叢に発現している消化管運動制御受容体と、それらをターゲットにした消化管機能改善薬 (2011)
  • Author(s): 上園保仁,須藤結香
  • Journal Title: 医学のあゆみ Volume: 238(10) Pages: 904-908
• [Journal Article] Possible involvement ofβ-endorphin in a loss of the coordinated balance ofμ-opioid receptors trafficking processes by fentanyl (2011)
  • Author(s): Imai, S., Sudo, Y., Nakamura, A., Ozeki, A., Asato, M., Hojo, M., Devi, L. A., Kuzumaki, N., Suzuki, T., Uezono, Y., Narita, M.
  • Journal Title: Synapse Volume: 65(9) Pages: 962-966
  • Peer Reviewed
• [Journal Article] がん患者の症状緩和のために-がん悪液質の予防、症状改善をめざす基礎医学研究 (2011)
  • Author(s): 上園保仁
  • Journal Title: がん患者と対症療法 Volume: 22(1) Pages: 58-63
• [Journal Article] Sevoflurane inhibits theμ-opioid receptor function expressed in Xenopus oocytes (2011)
  • Author(s): Minami, K., Sudo, Y., Yokoyama, T., Ogata, J., Takeuchi, M., Uezono, Y.
  • Journal Title: Pharmacology Volume: 88(3-4) Pages: 127-132
  • Peer Reviewed
• [Journal Article] Transcriptional up-regulation of cell surface Na_V1.7 sodium channels by insulin-like growth factor-1 via inhibition of glycogen synthase kinase-3βin adrenal chromaffin cells : enhancement of 22^Na^+influx, 45^Ca^<2+> influx and catecholamine secretion (2011)
  • Author(s): Yanagita, T., Satoh, S., Uezono, Y., Matsuo, K., Nemoto, T., Maruta, T., Yoshikawa, N., Iwakiri, T., Minami, K., Murakami, M.
  • Journal Title: Neuropharmacology Volume: 61(8) Pages: 1265-1274
  • Peer Reviewed
• [Journal Article] Effects of sevoflurane on voltage-gated sodium channel Na_v1.8, Na_v1.7, and Na_v1.4 expressed in Xenopus oocytes (2011)
  • Author(s): Yokoyama, T., Minami, K., Sudo, Y., Horishita, T., Ogata, J., Yanagita, T., Uezono, Y.
  • Journal Title: J Anesth Volume: 25(4) Pages: 609-613
  • Peer Reviewed
• [Journal Article] S(+)-ketamine suppresses desensitization ofγ-aminobutyric acid type B receptor-mediated signaling by inhibition of the interaction ofγ-aminobutyric acid type B receptors with G protein-coupled receptor kinase 4 or 5 (2011)
  • Author(s): Ando, Y., Hojo, M., Kanaide, M., Takada, M., Sudo, Y., Shiraishi, S., Sumikawa, K., Uezono, Y.
  • Journal Title: Anesthesiology Volume: 114(2) Pages: 401-411
  • Peer Reviewed
• [Journal Article] がん対策推進基本計画に基づく緩和ケア推進・研究の今後 (2010)
  • Author(s): 上園保仁
  • Journal Title: がん患者と対症療法 Volume: 21(2) Pages: 164-169
• [Journal Article] Activation of the neurokinin-1 receptor in rat spinal astrocytes induces Ca^<2+> release from IP_3-sensitive Ca^<2+> stores and extracellular Ca^<2+> influx through TRPC3 (2010)
  • Author(s): Miyano, K., Morioka, N., Sugimoto, T., Shiraishi, S., Uezono, Y., Nakata, Y.
  • Journal Title: Neurochem Int Volume: 57(8) Pages: 923-934
  • Peer Reviewed
• [Journal Article] Derived(mutated)-types of TRPV6 channels elicit greater Ca^<2+> influx into the cells than ancestral-types of TRPV6 : Evidence from Xenopus oocytes and mammalian cell expression system (2010)
  • Author(s): Sudo, Y., Matsuo, K., Tetsuo, T., Tsutsumi, S., Okura, M., Nakai, J., Uezono, Y.
  • Journal Title: J Pharmacol Sci Volume: 114(3) Pages: 281-291
  • Peer Reviewed
• [Journal Article] がん疼痛基礎医学研究-経験を科学- (2010)
  • Author(s): 上園保仁
  • Journal Title: がん患者と対症療法 Volume: 21(1) Pages: 78-79
• [Journal Article] Analysis of the effects of anesthetics and ethanol onμ-opioid receptor (2010)
  • Author(s): Minami, K., Sudo, Y., Shiraishi, S., Seo, M., Uezono, Y.
  • Journal Title: J Pharmacol Sci Volume: 112(4) Pages: 424-431
  • Peer Reviewed
• [Journal Article] Chronic lithium treatment up-regulates cell surface Na_V1.7 sodium channles via inhibition of glycogen synthase kinase-3 in adrenal chromaffin cells : enhancement of Na^+influx, Ca^<2+> influx and catecholamine secretion after lithium withdrawal (2009)
  • Author(s): Yanagita, T., Maruta, T., Nemoto, T., Uezono, Y., Matsuo, K., Satoh, S., Yoshikawa, N., Kanai, T., Kobayashi, H., Wada, A.
  • Journal Title: Neuropharmacology Volume: 57(3) Pages: 311-321
  • Peer Reviewed
• [Journal Article] Presence of GABA_B receptors forming heterodimers with GABA_<B1> and GABA_<B2> subunits in human lower esophageal sphincter (2009)
  • Author(s): Torashima, Y., Uezono, Y., Kanaide, M., Ando, Y., Enjoji, A., Kanematsu, T., Taniyama, K.
  • Journal Title: J Pharmacol Sci Volume: 111(3) Pages: 253-259
  • Peer Reviewed
• [Journal Article] 急速に世界に広まったTRPV6チャネル変異体のチャネル特性の解析-TRPV6クローン発現細胞を用いての解析- (2009)
  • Author(s): 上園保仁,須藤結香
  • Journal Title: 自律神経 Volume: 46(3) Pages: 190-197
• [Journal Article] 自律神経の薬理 (2009)
  • Author(s): 上園保仁
  • Journal Title: 自律神経 Volume: 46(3) Pages: 139-146
• [Journal Article] がん対策基本法とがん疼痛基礎医学研究 (2009)
  • Author(s): 上園保仁
  • Journal Title: がん患者と対症療法 Volume: 20(2) Pages: 71-73
• [Presentation] シグナルペプチド付加HaloTag-GPCRの細胞膜移行と機能的アッセイ (2012)
  • Author(s): 須藤結香,北條美能留,宮野加奈子,鈴木雅美,寺脇潔,白石成二,西田教行,上園保仁
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都市
  • Year and Date: 20120314-16
• [Presentation] The synergistic effects of herbal pungents 6-gingerol(6GC) 6-shogaol(6SG) and hydroxyα-sanshool(HAS) on in vitro peristaltic motility of isolated rat colon : Lessons from the unique prokinetic activity of Japanese traditional medicine daikenchuto (2011)
  • Author(s): Ohtake, N., Ikemura R., Ohbuchi, K., Sudo, Y., Uezono, Y., Yamamoto, M.
  • Organizer: Digestive Disease Week2011
  • Place of Presentation: Chicago, U. S. A.
  • Year and Date: 20110507-10
• [Presentation] ラベルフリーで細胞機能をアッセイできるシステム、CellKeyTMを用いた各種GPCR, lon channelの活性評価 (2011)
  • Author(s): 上園保仁,須藤結香,宮野加奈子,柏瀬陽平,澤田祐美,寺脇潔,鈴木雅美,小柳尚史,白石成二,樋上賀一,西田教行
  • Organizer: 第64回日本薬理学会西南部会
  • Place of Presentation: 福岡市
  • Year and Date: 2011-11-20
• [Presentation] 患者さんのQOL向上を目指して:基礎研究を臨床に生かすための試み (2010)
  • Author(s): 上園保仁
  • Organizer: 第4回日本緩和医療薬学会年会
  • Place of Presentation: 鹿児島
  • Year and Date: 20100925-26
• [Presentation] Development of a rat model for cancerous peritonitis pain (2010)
  • Author(s): Suzuki, M., Matoba, M., Sasaki, H., Terawaki, K., Shiraishi, S., Uezono, Y.
  • Organizer: 13th World Congress on Pain
  • Place of Presentation: Montoreal, Canada
  • Year and Date: 20100829-0902
• [Presentation] Cellular signaling and internalization profiles of heterodimerized cannabinoid CB1 and opioid M receptors : Implication of cannabinoid and opioid interaction at the receptor levels (2010)
  • Author(s): Hojo, M., Sudo, Y., Ando, Y., Takada, Y., Uezono, Y., Sumikawa, K.
  • Organizer: International Anesthesia Research Society 2010 Annual Meeting
  • Place of Presentation: Honolulu, U. S. A
  • Year and Date: 20100320-23
• [Presentation] Internalization and recycling profiles ofμ-and dimerizedμ-δopioid receptors induced by remifentanil : implication of acute tolerance of remifentanil (2010)
  • Author(s): Ando, Y., Murata, H., Kurata, S., Hojo, M., Sumikawa, K., Uezono, Y.
  • Organizer: International Anesthesia Research Society 2010 Annual Meeting
  • Place of Presentation: Honolulu, U. S. A.
  • Year and Date: 20100320-23
• [Presentation] シンポジウム「統合医療」緩和ケア推進から3年-緩和医療研究における基礎医学の役割:経験を科学に (2010)
  • Author(s): 上園保仁
  • Organizer: 第16回日本行動医学会学術総会
  • Place of Presentation: 鹿児島市
  • Year and Date: 20100226-27
• [Presentation] 「緩和医療による生活の質向上を求めて-基礎から臨床まで根拠を踏まえた情報提供のありかたを探る-」緩和医療による患者さんの生活向上を目指して-基礎医学者のできること (2009)
  • Author(s): 上園保仁
  • Organizer: 第19回日本医療薬学会年会
  • Place of Presentation: 長崎市
  • Year and Date: 20091024-25