Concentration-related metabolic rate and behavioral thermoregulatory adaptations to serial administrations of nitrous oxide in rats

Abstract

BackgroundInitial administration of ≥60% nitrous oxide (N2O) to rats evokes hypothermia, but after repeated administrations the gas instead evokes hyperthermia. This sign reversal is driven mainly by increased heat production. To determine whether rats will behaviorally oppose or assist the development of hyperthermia, we previously performed thermal gradient testing. Inhalation of N2O at ≥60% causes rats to select cooler ambient temperatures both during initial administrations and during subsequent administrations in which the hyperthermic state exists. Thus, an available behavioral response opposes (but does not completely prevent) the acquired hyperthermia that develops over repeated high-concentration N2O administrations. However, recreational and clinical uses of N2O span a wide range of concentrations. Therefore, we sought to determine the thermoregulatory adaptations to chronic N2O administration over a wide range of concentrations.MethodsThis study had two phases. In the first phase we adapted rats to twelve 3-h N2O administrations at either 0%, 15%, 30%, 45%, 60% or 75% N2O (n = 12 per group); outcomes were core temperature (via telemetry) and heat production (via respirometry). In the second phase, we used a thermal gradient (range 8°C—38°C) to assess each adapted group’s thermal preference, core temperature and locomotion on a single occasion during N2O inhalation at the assigned concentration.ResultsIn phase 1, repeated N2O administrations led to dose related hyperthermic and hypermetabolic states during inhalation of ≥45% N2O compared to controls (≥ 30% N2O compared to baseline). In phase 2, rats in these groups selected cooler ambient temperatures during N2O inhalation but still developed some hyperthermia. However, a concentration-related increase of locomotion was evident in the gradient, and theoretical calculations and regression analyses both suggest that locomotion contributed to the residual hyperthermia.ConclusionsAcquired N2O hyperthermia in rats is remarkably robust, and occurs even despite the availability of ambient temperatures that might fully counter the hyperthermia. Increased locomotion in the gradient may contribute to hyperthermia. Our data are consistent with an allostatic dis-coordination of autonomic and behavioral thermoregulatory mechanisms during drug administration. Our results have implications for research on N2O abuse as well as research on the role of allostasis in drug addiction.

Validation of an equation for energy expenditure that does not require the respiratory quotient

“…Finally, our study also lends credence to the use of the Weir RQ - method in previous research involving measurement of EE during exposure to nitrous oxide, a gas that interferes with CO 2 sensing [18–26].…”

“…The second insight, a corollary of the first, is that if F i O 2 deviates substantially from normoxia, then Eq 5 will agree less well with the standard method. It should be noted in this context that F i O 2 can be generated at a ‘customized’ value by blending gases with precision flow controllers, e.g., as in [18–26].…”

An Overview of the Implications for Perianesthesia Nurses in terms of Intraoperative Changes in Temperature and Factors Associated with Unintentional Postoperative Hypothermia

“…Phase II (heat transfer from the warmer perimeter to the rest of the environment) is characterised by a gradual linear decrease that occurs over a period of 2-4 hours, during which thermal loss surpasses metabolic heat generation [ 39 – 41 ]. Phase III (thermal homeostasis) starts following 3 - 4 h, once CTs of 33 to 35 degrees Celsius cause peripheral vasoconstriction [ 42 , 43 ]. Neuraxial anaesthesia, like generalized anaesthesia, interferes with physiologic thermoregulation, but it does so via a different mechanism.…”

Individual differences in biological regulation: Predicting vulnerability to drug addiction, obesity, and other dysregulatory disorders.

“…Accordingly, in tolerant individuals, the regulated variable should return close to baseline levels with a tendency for some residual bias in the direction of the initial drug effect. Dworkin (1993, p. xiv) clearly described this widely held belief about chronic drug tolerance by stating “the everyday observation that even with very many administrations, drug effects sometimes diminish to zero but do not invert to the opposite.” However, empirical data (Kaiyala & Ramsay, 2018; Ramsay, Kaiyala, et al, 2005) indicate that this model is overly simplistic and that underlying effector responses can persistently overcompensate for the effect of the disturbance caused by the continued action of the drug. Chronically “tolerant” individuals can in fact exhibit persistent allostatic sign reversals (inversions) of the regulated variable in the opposite direction to the initial drug effect, and this can occur despite the presence of maximal drug concentrations (i.e., these reversals are not drug-withdrawal phenomena).…”

“…RMAV contends that reliable individual differences in an individual’s regulatory responses to a drug disturbance are the common factor that accounts for this association. Figure 1F illustrates the results from a dose-effect study of tolerance development to N 2 O-induced hypothermia over 12 sessions using nonselected rats (Kaiyala & Ramsay, 2018). On average, outbred rats exhibit an initial N 2 O-induced hypo thermia when administered 45–75% N 2 O, but over repeated exposures an allostatic sign-reversal hyper thermia (i.e., exceeds fully tolerant levels) develops.…”