Robust thermoregulatory overcompensation, rather than tolerance, develops with serial administrations of 70% nitrous oxide to rats
Robust thermoregulatory overcompensation, rather than tolerance, develops with serial administrations of 70% nitrous oxide to rats
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DOI：
10.1016/j.jtherbio.2011.10.004
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发表时间：
2012-01-01
影响因子：
2.7
通讯作者：
Ramsay, Douglas S.
中科院分区：
文献类型：
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作者：
Kaiyala, Karl J.;Chan, Ben;Ramsay, Douglas S.
给药后典型全动物因变量的变化代表了药物药理作用、个体对由此产生的干扰的自主神经和行为反应以及许多其他影响的整体。一个典型的例子是核心温度（T-c），长期用于量化反复给药后的初始药物敏感性和耐受性获得。我们之前的研究表明，对一氧化二氮（N2O）诱导的低温初始敏感性不同的大鼠在不同的N2O处理中表现出不同的耐受性发展模式。具体来说，我们假设具有初始不敏感表型的大鼠随后会发展出调节过度补偿，从而介导非稳态高温状态，而具有初始敏感表型的大鼠随后会补偿到稳态恒温状态。为了避免操作和侵入性操作造成的混淆，该预测的有效测试需要通过植入的遥测温度传感器进行非侵入性热测量，结合直接和间接量热法，以及自动给药，以实现可重复的稳态给药。我们筛选了237只成年大鼠对70% n2o诱导的低温的初始敏感性。30只在筛选时表现出明显体温过低的高度敏感大鼠和30只最初表现出轻微体温过低的高度不敏感大鼠被随机分为三组（每组n=10），接受：(1)12次使用经典条件反射法暴露在70% N2O环境中90分钟，(2)12次使用随机对照条件反射法暴露在70% N2O环境中90分钟，或(3)接受定制空气的无药物对照组。在N2O和对照气体处理期间，代谢产热（通过间接量热法）、体热损失（通过直接量热法）和T-c（通过遥测法）同时被量化。最初不敏感的大鼠（第三次给药）在N2O给药期间迅速获得了显著的适应高温表型，而最初敏感的大鼠在第4和第5次吸入N2O时表现出经典耐受（常温）。然而，在第11次和第12次N2O处理期间，敏感大鼠随后获得了高热表型，并与最初不敏感的大鼠无法区分。热疗的主要机制是代谢产热的迅速增加。然而，我们没有得到热反应的经典条件作用的证据。我们得出的结论是，对N2O诱导的低温的初始敏感程度预测了重复N2O给药过程中热适应的时间模式，但最初不敏感和敏感的动物最终会趋同于由超代偿产热介导的给药内热疗的相似（且大量）幅度。(C) 2011 Elsevier Ltd.版权所有。
Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug's pharmacological effect, the individual's autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature (T-c), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N2O)-induced hypothermia would exhibit different patterns of tolerance development across N2O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non-invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N2O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups (n=10 each/group) that received: (1) twelve 90-min exposures to 70% N2O using a classical conditioning procedure, (2) twelve 90-min exposures to 70% N2O using a random control procedure for conditioning, or (3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and T-c (via telemetry) were simultaneously quantified during N2O and control gas administrations. Initially insensitive rats rapidly acquired (3rd administration) a significant allostatic hyperthermic phenotype during N2O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N2O inhalation in the 4th and 5th sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11th and 12th N2O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N2O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N2O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production. (C) 2011 Elsevier Ltd. All rights reserved.