Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats

Kaiyala, Karl J.; Butt, Shehzad; Ramsay, Douglas S.

doi:10.1007/s00213-006-0655-1

Cited by 12 publications

(48 citation statements)

References 46 publications

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“…We speculate that the capacity for this putative thermoregulatory response remains largely unimpaired at 30 and 50% N 2 O, whereas it is impaired in most animals at 60 and 75% N 2 O. Initial drug insensitivity and drug tolerance In a companion paper (Kaiyala et al 2007), we demonstrate that the mechanism of chronic tolerance development to hypothermia induced by 60% N 2 O involves the acquisition of increased HP during drug administration, which overcomes the effect of the drug to augment HL (N 2 O appears to retain its heat dissipating effect across drug administrations). Thus, in our model, initial drug insensitivity and chronic drug tolerance are phenomena united by a common mechanism: An active response effectively counters an ongoing drug effect.…”

Section: Increased Heat Dissipation: a Primary N 2 O Effectmentioning

confidence: 97%

“…It should be noted that T core has been widely used by drug researchers both to define sensitivity and study tolerance, most notably in the ethanol field (Browman et al 2000;Palmer et al 2002;Lovinger and Crabbe 2005). At concentrations ≥60%, initial administrations of N 2 O typically evoke significant hypothermia, but it is important to emphasize that its magnitude exhibits considerable and reliable individual differences (Ramsay et al 1999Kaiyala et al 2001;Kaiyala and Ramsay 2005;Kaiyala et al 2007). The time integral of HP minus HL determines changes of T core , and the detailed temporal dynamics of the three variables can be rigorously and synchronously quantified via indirect calorimetry, direct gradient layer calorimetry, and telemetry, respectively.…”

Section: Introductionmentioning

confidence: 97%

“…The use of simultaneous direct and indirect calorimetry both with and without simultaneous measurements of T core is a well-established methodology in thermoregulatory physiology (Caldwell et al 1966;Sugano 1983;Rumpler and Seale 1997;Webb 1997;Robinson and Fuller 1999a,b;Gordon et al 2003) but has not been exploited heretofore in studies on initial drug sensitivity. In a companion paper, we employed the model to study tolerance to N 2 O hypothermia in rats and demonstrated that the tolerant state is characterized by robust compensation by increased HP for continued pharmacological sensitivity at the level of HL (Kaiyala et al 2007). It has been hypothesized previously that regulatory compensation may also blunt the impact of the pharmacological effect on a monitored dependent variable even within an initial drug administration (Haefely 1986).…”

Section: Introductionmentioning

confidence: 98%

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Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Kaiyala

Ramsay

2007

Psychopharmacology

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Section: Increased Heat Dissipation: a Primary N 2 O Effectmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

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Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Kaiyala

Ramsay

2007

Psychopharmacology

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“…19,20 Increases in HP can occur during the course of an initial N 2 O administration and result in the development of acute tolerance, 19 while progressive increases in HP over subsequent N 2 O administrations result in the development of chronic tolerance. 21,22 …”

Section: Introductionmentioning

confidence: 99%

“…The magnitude of the HP response increases progressively over repeated N 2 O administrations, which contributes to chronic tolerance development, and with additional administrations causes rats to eventually exhibit a hyperthermic overcompensation of Tc. 21,22,29 …”

Section: Introductionmentioning

confidence: 99%

Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors

2014

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Initial administration of 60% nitrous oxide (N2O) to rats at an ambient temperature of 21°C decreases core temperature (Tc), primarily via increased heat loss (HL). Over repeated N2O administrations, rats first develop tolerance to this hypothermia and subsequently exhibit hyperthermia (a sign-reversal) due primarily to progressive increases in heat production (HP). When rats initially receive 60% N2O in a thermal gradient, they become hypothermic while selecting cooler ambient temperatures that facilitate HL. This study investigated whether rats repeatedly administered 60% N2O in a thermal gradient would use the gradient to behaviorally facilitate, or oppose, the development of chronic tolerance and a hyperthermic sign-reversal. Male Long-Evans rats (N = 16) received twelve 3-h administrations of 60% N2O in a gas-tight, live-in thermal gradient. Hypothermia (Sessions 1–3), complete chronic tolerance (Sessions 4–6), and a subsequent transient hyperthermic sign-reversal (Sessions 7–12) sequentially developed. Despite the progressive recovery and eventual hyperthermic sign-reversal of Tc, rats consistently selected cooler ambient temperatures during all N2O administrations. A final 60% N2O administration in a total calorimeter indicated that the hyperthermic sign-reversal resulted primarily from increased HP. Thus, rats did not facilitate chronic tolerance development by moving to warmer locations in the gradient, and instead selected cooler ambient temperatures while simultaneously increasing autonomic HP. The inefficient concurrent activation of opposing effectors and the development of a sign-reversal are incompatible with homeostatic models of drug-adaptation and may be better interpreted using a model of drug-induced allostasis.

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Direct animal calorimetry, the underused gold standard for quantifying the fire of life

Kaiyala

Ramsay

2011

Comparative Biochemistry and Physiology Part A: Molecular &

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Direct animal calorimetry, the gold standard method for quantifying animal heat production (HP), has been largely supplanted by respirometric indirect calorimetry owing to the relative ease and ready commercial availability of the latter technique. Direct calorimetry, however, can accurately quantify HP and thus metabolic rate (MR) in both metabolically normal and abnormal states, whereas respirometric indirect calorimetry relies on important assumptions that apparently have never been tested in animals with genetic or pharmacologically-induced alterations that dysregulate metabolic fuel partitioning and storage so as to promote obesity and/or diabetes. Contemporary obesity and diabetes research relies heavily on metabolically abnormal animals. Recent data implicating individual and group variation in the gut microbiome in obesity and diabetes raise important questions about transforming aerobic gas exchange into HP because 99% of gut bacteria are anaerobic and they outnumber eukaryotic cells in the body by ~10-fold. Recent credible work in non-standard laboratory animals documents substantial errors in respirometry-based estimates of HP. Accordingly, it seems obvious that new research employing simultaneous direct and indirect calorimetry (total calorimetry) will be essential to validate respirometric MR phenotyping in existing and future pharmacological and genetic models of obesity and diabetes. We also detail the use of total calorimetry with simultaneous core temperature assessment as a model for studying homeostatic control in a variety of experimental situations, including acute and chronic drug administration. Finally, we offer some tips on performing direct calorimetry, both singly and in combination with indirect calorimetry and core temperature assessment.

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Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats

Cited by 12 publications

References 46 publications

Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors

Direct animal calorimetry, the underused gold standard for quantifying the fire of life

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