Clinically Relevant Infusion Rates of μ-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Botzinger Complex Region
Clinically Relevant Infusion Rates of μ-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Botzinger Complex Region
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DOI：
10.1152/jn.00188.2009
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发表时间：
2010-01-01
影响因子：
2.5
通讯作者：
Zuperku, Edward J.
中科院分区：
文献类型：
--
作者：
Mustapic, Sanda;Radocaj, Tomislav;Zuperku, Edward J.
Mustapic S，Radocaj T，Sanchez A，Dogas Z，Stucke AG，Hopp FA，Stuth EA，Zuperku EJ.μ-阿片激动剂瑞芬太尼的临床相关输注速率导致去大脑犬呼吸缓慢，但不是通过对前Brotzinger复合区的直接影响。J Neurophysiol 103：409-418，2010.首次发表于2009年11月11日; doi：10.1152/jn.00188.2009。用于镇痛的临床剂量的μ-阿片样物质的全身给药通常减慢呼吸速率。前Botzinger复合体（pre-BotC）呼吸神经元上的μ阿片受体（MORs）是呼吸节律发生的潜在靶点。本研究的目的是确定前BotC MORs的贡献，在体内产生的呼吸徐缓的临床相关的输注速率的瑞芬太尼（雷米），短效，有效的μ阿片类镇痛药的静脉内给药。在去大脑的狗中，使用多管微量移液器记录前BotC神经元活动，并排出阿片拮抗剂纳洛酮（NAL，0.5 mM）、谷氨酸激动剂D-高半胱氨酸（DLH，20 mM）或莫尔激动剂[D-Ala（2）、N-Me-Phe（4）、gly-ol（5）]-脑啡肽（DAMGO，100 μ M）。从膈神经图测量吸气和呼气持续时间（T-I和T-E）和膈神经活动峰值（PPA）。通过其对DLH显微注射的速率改变反应（通常为呼吸急促）在功能上鉴定前BotC。在静脉注射雷米普利诱导的呼吸徐缓期间（类似于中枢呼吸频率f（B）降低60%），BotC前双侧注射NAL并不改变T-I、T-E、f（B）和PPA。此外，NAL picoemitted到单个前BotC神经元静脉注射雷米抑郁症没有影响他们的放电。与此相反，类似于60 μ g/kg的静脉NAL迅速逆转所有雷米诱导的效果。在另一组狗中，在预BotC中微量注射DAMGO使f（B）增加44%，而随后的静脉内雷米输注超过抵消这种DAMGO诱导的呼吸急促。这些结果表明，引起深度镇痛的血浆浓度的μ-阿片样物质通过位于前BotC区域外的M0 R产生其呼吸徐缓效应。
Mustapic S, Radocaj T, Sanchez A, Dogas Z, Stucke AG, Hopp FA, Stuth EA, Zuperku EJ. Clinically relevant infusion rates of mu-opioid agonist remifentanil cause bradypnea in decerebrate dogs but not via direct effects in the pre-Brotzinger Complex region. J Neurophysiol 103: 409-418, 2010. First published November 11, 2009; doi: 10.1152/jn.00188.2009. Systemic administration of mu-opioids at clinical doses for analgesia typically slows respiratory rate. Mu-opioid receptors (MORs) on pre-Botzinger Complex (pre-BotC) respiratory neurons, the putative kernel of respiratory rhythmogenesis, are potential targets. The purpose of this study was to determine the contribution of pre-BotC MORs to the bradypnea produced in vivo by intravenous administration of clinically relevant infusion rates of remifentanil (remi), a short-acting, potent mu-opioid analgesic. In decerebrate dogs, multibarrel micropipettes were used to record preBotC neuronal activity and to eject the opioid antagonist naloxone (NAL, 0.5 mM), the glutamate agonist D-homocysteic acid (DLH, 20 mM), or the MOR agonist [D-Ala(2), N-Me-Phe(4), gly-ol(5)]-enkephalin (DAMGO, 100 mu M). Inspiratory and expiratory durations (T-I and T-E) and peak phrenic nerve activity (PPA) were measured from the phrenic neurogram. The pre-BotC was functionally identified by its rate altering response (typically tachypnea) to DLH microinjection. During intravenous remi-induced bradypnea (similar to 60% decrease in central breathing frequency, f(B)), bilateral injections of NAL in the pre-BotC did not change T-I, T-E, f(B), and PPA. Also, NAL picoejected onto single pre-BotC neurons depressed by intravenous remi had no effect on their discharge. In contrast, similar to 60 mu g/kg of intravenous NAL rapidly reversed all remi-induced effects. In a separate group of dogs, microinjections of DAMGO in the pre-BotC increased f(B) by 44%, while subsequent intravenous remi infusion more than offset this DAMGO induced tachypnea. These results indicate that mu-opioids at plasma concentrations that cause profound analgesia produce their bradypneic effect via MORs located outside the pre-BotC region.