研究內容主要探討NMDA受體在體內的生病理角色，尤其是了解藥毒物在體內產生的作用機制中，NMDA受體參與的作用，成果包括：
我們發現許多內生性胜肽如nociceptin[1]、amyloid beta peptide(Aβ) [2]以及外來物質如鉛離子[3]和氧化壓力[4]等因子會經由影響興奮性神經傳遞物質的傳遞過程或受體的反應性，改變脊髓交感節前神經元(sympathetic preganglionic neuron, SPN)之活性。亦發現CART peptide (Cocaine and Amphetamine-Regulated Transcript，古柯鹼和安非他命調控之轉錄因子)參與前腹外側延腦(RVLM)區域神經元對心血管功能的調節作用，且此作用因大鼠品系不同而有差異[5]。而濫用藥物甲基安非他命引發的心血管毒性作用亦與前腹外側延腦(RVLM)區域麩胺酸受體(NMDA受體和mGluR5受體)的活化有關[6]。
[1] Lai C-C, Wu SY, Chen C-T, Dun NJ (2000) Nociceptin inhibits rat sympathetic preganglionic neurons in situ and in vitro.Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278, R592-R597.
[2] Lai C-C, Lo H, Lin HG, Lin HH (2019) Potentiation of NMDA-mediated responses by amyloid beta-peptide 1-40 in rat sympathetic preganglionic neurons. J. Alzheimers Dis. 67, 1291-1303.
[3] Lai C-C, Lin HH, Chen C-W, Chen S-H, Chiu TH (2002) Excitatory action of lead on rat sympathetic preganglionic neurons in vitro and in vivo. Life Sci. 71, 1035-1045.
[4] Lin HH, Chen C-H, Hsieh W-K, Chiu TH, Lai C-C (2003) Hydrogen peroxide increases the activity of rat sympathetic preganglionic neurons in vivo and in vitro. Neuroscience 121, 641-647.
[5] Lai C-C, Yuan Z-F, Chu L-Y, Chuang K-T, Lin H-H (2019) Roles of cocaine- and amphetamine-regulated transcript peptide in the rostral ventrolateral medulla in cardiovascular regulation in rats. Brain Res. 1710, 117-124.
[6] Lai C-C, Fang C, Kuo CY, Wu YW, Lin HH (2020) Activation of mGluR5 and NMDA receptor pathways in the Rostral Ventrolateral Medulla as a Central Mechanism for Methamphetamine-Induced Pressor Effect in Rats. Biomolecules 10, 149.
我們發現乙醇對中樞交感神經元NMDA受體活性的影響與乙醇暴露的劑量以及時間有關。急性投與乙醇劑量依賴性的抑制交感神經元上NMDA受體之反應性；但當延長乙醇暴露時間，乙醇對NMDA受體活性的抑制作用會降低，亦即產生急性耐受性[7, 8]。我們發現該作用的機制為：延長乙醇暴露時間會活化特定訊息分子或代謝性麩胺酸受體及下游訊息分子，進而改變NMDA受體的活性(磷酸化狀態)，導致NMDA受體對乙醇的敏感性降低[9-12]。近期實驗亦發現延腦區的NMDA受體及相關的訊息分子如一氧化氮在急性乙醇引發的心血管功能異常(心跳過速以及低血壓)扮演重要的角色[13-15]。
[7] Lin HH, Hsieh W-K, Shiu J-Y, Chiu TH, Lai C-C (2003) Inhibition by ethanol of NMDA-induced responses and acute tolerance to the inhibition in rat sympathetic preganglionic neurons in vitro and in vivo. Br. J. Pharmacol. 140, 955-963.
[8] Lai C-C, Chang M-C, Lin HH (2004) Acute tolerance to ethanol Inhibition of NMDA-induced responses in rat rostral ventrolateral medulla neurons. J. Biomed. Sci. 11, 482-492.
[9] Lin HH, Chang S-J, Shie H-J, Lai C-C (2006) Ethanol inhibition of NMDA-induced responses and acute tolerance to the inhibition in rat rostral ventrolateral medulla in vivo: involvement of cAMP-dependent protein kinases. Neuropharmacology 51, 747-755.
[10] Hsieh W-K, Lin H-H, Lai C-C (2009) Involvement of protein kinase C and Src tyrosine kinase in acute tolerance to ethanol inhibition of spinal NMDA-induced pressor responses in rats. Br. J. Pharmacol. 158, 806-818.
[11] Keng N-T, Lin H-H, Hsieh W-K, Lin H-R, Lai C-C (2012) Dual regulation by ethanol of the inhibitory effects of ketamine on spinal NMDA-induced pressor responses in rats. J. Biomed. Sci. 19, 11.
[12] Lai C-C, Hsu J-W, Cheng Y-S, Lin H-H (2019) Involvement of metabotropic glutamate receptor 5 in ethanol regulation of NMDA receptor activity in rat substantia gelatinosa neurons. Life Sci. 233, 116729.
[13] Lin HH, Cheng TT, Lo H, Lin YC, Lai C-C (2018) Spontaneously hypertensive rats exhibit higher sensitivity to ethanol-induced hypotensive effects: role of NMDA receptors and nitric oxide in rostral ventrolateral medulla. Alcohol 73, 25-35.
[14] Lo H, Lin HH, Chen JK, Stiumorang JH, Lai C-C (2018) Involvement of NMDA receptors, nitric oxide and GABA in rostral ventrolateral medulla in acute ethanol-induced cardiovascular responses in rats. Alcohol. Clin. Exp. Res. 42, 1418-1430.
[15] Situmorang JH, Lin HH, Lo H, Lai C-C (2018) Role of neuronal nitric oxide synthase (nNOS) at medulla in tachycardia induced by repeated administration of ethanol in conscious rats. J. Biomed. Sci. 25, 8.
目前許多證據顯示在傳入脊髓背角的神經纖維上具有許多內生性的CART peptide。以閃尾試驗(tail-flick test)發現脊髓內注射CART peptide選擇性的增強NMDA所引發的熱痛覺過敏；在大鼠背角神經細胞所做的離體電生理研究亦顯示CART peptide選擇性的增強NMDA引發的去極化反應[16]。進一步之研究發現CART peptide可能經由PKA和PKC訊息路徑，增加NMDA受體NR1次單位的磷酸化，進而增加NMDA受體的反應性[17]。CART peptide活化NMDA受體的作用具年齡相關性，對出生二週後的大鼠方有增強作用，且而活化NMDA受體會再引發ERK訊息路徑的活化[18]。這些結果指出，CART peptide可調節痛覺神經元上NMDA受體和ERK訊息路徑，在體內痛覺的傳遞上扮演重要角色。
[16] Lin HH, Chiu H-Y, Lai C-C (2005) Potentiation of spinal N-methyl-D-aspartate-mediated nociceptive transmission by cocaine-regulated and amphetamine-regulated transcript peptide in rats. NeuroReport 16, 253-257.
[17] Chiu H-Y, Lin H-H, Lai C-C (2009) Potentiation of spinal NMDA-mediated nociception by cocaine- and amphetamine-regulated transcript peptide via PKA and PKC signaling pathways in rats. Regul. Pept. 158, 77-85.
[18] Chiu H-Y, Lin H-H, Lai C-C (2010) Cocaine- and amphetamine-regulated transcript (CART) peptide activates ERK pathways via NMDA receptors in rat spinal cord dorsal horn in an age-dependent manner. Regul. Pept. 164, 90-96.