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Sleep apnea, hypertension, atherosclerosis, and obesity are features of metabolic syndrome associated with decreased restorative sleep and increased pain. These traits are relevant for anesthesiology because they confer increased risks of a negative anesthetic outcome. This study tested the one-tailed hypothesis that rats bred for low intrinsic aerobic capacity have enhanced nociception and disordered sleep.
Rats were from a breeding strategy that selected for low aerobic capacity runners (LCR) and high aerobic capacity runners (HCR). Four different phenotypes were quantified. Rats (n=12) underwent von Frey sensory testing, thermal nociceptive testing (n=12), electrographic recordings of sleep and wakefulness (n=16), and thermal nociceptive testing before and for six weeks after a unilateral chronic neuropathy of the sciatic nerve (n=14).
Paw withdrawal latency to a thermal nociceptive stimulus was significantly (P<0.01) less in LCR than HCR rats. There were significant differences in sleep. LCR rats spent significantly (P<0.01) more time awake (18%) and less time in non-rapid eye movement sleep (−19%) than HCR rats. Non-rapid eye movement sleep episodes were of shorter duration (−34%) in LCR than HCR rats. Rapid eye movement sleep of LCR rats was significantly more fragmented than Rapid eye movement sleep of HCR rats. LCR rats required two weeks longer than HCR rats to recover from peripheral neuropathy.
Rodents with low aerobic capacity exhibit features homologous to human metabolic syndrome. This rodent model offers a novel tool for characterizing the mechanisms through which low aerobic function and obesity might confer increased risks for anesthesia.
Metabolic syndrome and associated co-morbidities have special relevance for anesthesiology.1–3 Central obesity is a feature of metabolic syndrome which confers an increased risk of type II diabetes,4 and the combination of obesity and diabetes is associated with increased perioperative risks.5–7 Obesity increases risk for aspiration during induction,8 decreases perioperative tissue oxygenation,9 is a predictor for difficult mask ventilation,10 and is a risk factor for anesthesia-related maternal mortality.11 Metabolic syndrome also is associated with poor sleep,12–20 and disrupted sleep can contribute to metabolic syndrome.13,17–19,21,22 Metabolic syndrome increases risk for chronic neuropathic pain,23 and sleep disruption enhances pain perception.24–28
The complexity and bi-directional nature of the foregoing pathologies emphasize the need for animal models that can help elucidate mechanisms underlying the interactions between metabolic syndrome, sleep, and pain. Two broad observations suggest that aerobic capacity and its attendant subordinate phenotypes are critical in the divide between health and disease, and motivated the development of rat models of disease risk. First, clinical studies reveal a strong statistical relationship between dysfunctional oxygen metabolism and all-cause morbidity and mortality. Indeed, for both healthy individuals and those with cardiovascular disorders low exercise capacity is a stronger predictor of decreased survival compared to other conventional risk factors such as body mass index, smoking, hypertension, dyslipidemia, or diabetes.29 Second, exercise is an effective prescription for a surprisingly wide range of chronic diseases.30
These ideas formed the basis for speculating that experimental models that divide for health and disease could be created by selection for low and high intrinsic aerobic endurance running capacity. Starting from a genetically heterogeneous population of rats developed at the National Institutes of Health, a divergent (two-way) artificial selection process was used to generate lines of low aerobic capacity runners (LCR) and high aerobic capacity runners (HCR).31 At 10 generations of selection the two lines divided widely for both the expected running capacity and the hypothesized differences for health risks including metabolic syndrome.32
Development of LCR and HCR lines generated a unique model system for dissection of aerobic endurance capacity and its correlated health-related phenotypes. The major hypothesis is that functional alleles at multiple interacting loci that affect intrinsic aerobic capacity have been enriched or fixed differentially between the LCR and HCR lines. It is critical that the models are maintained as genetically heterogeneous lines by using a mating paradigm that minimizes inbreeding.31 Compared to inbred strains, in which essentially all loci have been taken to fixation, outbred selected lines maintain genetic complexity which allows combinations of allelic variants at multiple interacting loci to be enriched by selection pressure.33 As a result, the LCR-HCR model is better suited to discover epistatic interactions, modifier genes, and synergistic actions.34 Importantly, the concurrent breeding of the LCR and HCR rats at every generation allows the lines to serve as reciprocal controls for unknown environmental changes.
The present study tested the hypothesis that LCR rats, in addition to a predisposition for metabolic syndrome,32,35 also have altered nocioception and disrupted sleep. The results are consistent with the notion that low intrinsic aerobic capacity and attendant correlated traits such as obesity can at least partly underlie pathology associated with altered nocioception and disrupted sleep.
Experiments were conducted in accordance with the Policy on Humane Care and Use of Laboratory Animals established by the National Institutes of Health (publication 80-23). All procedures were reviewed and approved by the University of Michigan Committee on Use and Care of Animals (Ann Arbor, Michigan). This study used a recently developed rat model selectively bred as low aerobic capacity runners and high aerobic capacity runners. These rats were derived from a genetically heterogeneous founder population developed at the National Institutes of Health.36 As described in detail previously,31 a large-scale rotational breeding strategy was started in 1996 to develop lines of rats that differ for intrinsic (i.e., untrained) aerobic capacity and retain wide heterogeneity. Each rat in the founder population (96 males and 96 females) was tested for maximal endurance running capacity on a speed-ramped treadmill. This test was patterned after clinical treadmill running tests and provided a reliable estimate of aerobic capacity (VO2 max) to segregate rats into the lowest and highest capacity runners. Twenty-six mating pairs were selected to create 13 base families of LCR and 13 base families of HCR. Offspring arising from these low and high breeder animals were tested at 11 weeks of age for intrinsic (i.e., untrained) running capacity. The highest performing male and female in each HCR family and the lowest performing male and female from each LCR family served as parents for each subsequent generation. After 11 generations of selective breeding, HCR and LCR rats differed by almost 350% for endurance running capacity and LCR rats exhibited several features consistent with metabolic syndrome.32
Rats used in the present study were males from generations 20 and greater. Differences in body weight between HCR and LCR rats are illustrated by Figs. 1A and B. Typical weights ranged from about 380 g (HCR) to 550 g (LCR). The difference in aerobic phenotype of distance run to exhaustion by HCR and LCR rats has been quantified for generation 26 and is illustrated by figure 1C. Two key points are that 1) these rats were never exercise trained and 2) this breeding procedure made it possible for the present study to evaluate the impact of genetically segregated intrinsic capacity for oxygen metabolism on nociception and sleep. Table 1 summarizes some of the previously documented physiological, behavioral, and metabolic differences between HCR and LCR rats.
There is a convergence of evidence that sleep neurobiology can help elucidate some of the mechanisms by which anesthetics cause a loss of wakefulness (reviewed in37–41). Therefore, the goal of experiment 1 was to phenotype states of sleep and wakefulness as a prelude to future studies designed to characterize responses of HCR and LCR rats to intravenous and volatile anesthetics. The procedures used to study sleep in rats have been described in detail.42,43 Briefly, eight male HCR rats and eight male LCR rats were anesthetized with 3% isoflurane in 100% O2 delivered at a flow rate of 1 l/min. Delivered isoflurane concentration was measured by spectrometry (Cardiocap™/5, Datex-Ohmeda, Louisville, CO). Once anesthetized, each rat was placed in a Kopf Model 962 small animal stereotaxic frame with a Model 906 rat anesthesia mask (David Kopf Instruments, Tujunga, CA) and delivered isoflurane concentration was decreased to 1.5%. Core body temperature was maintained at 37°C throughout the surgical procedure with the use of a re-circulating heat pump (Gaymar Industries, Orchard Park, NY). A midline scalp incision was made and electrodes were implanted for recording the electroencephalogram and electromyogram. The cortical electroencephalogram electrodes (8IE36320SPCE; Plastics One, Roanoke, VA) were screwed into the cranium at three different sites relative to bregma: 2.0 mm posterior, 1.3 mm lateral; 2.0 mm posterior, −1.5 mm lateral; and 1.0 mm anterior, 1.5 mm lateral. Two electromyogram electrodes were constructed from AS632 biomed wire (4.5 cm length, Cooner Wire Company, Chatsworth, CA) and were placed into the dorsal neck muscles. Another electrode was placed subcutaneously near the dorsal aspect of the skull and served as an indifferent electrode. Leads from all six electrodes were placed together in a six-pin multi-channel electrode pedestal (MS363, Plastics One) that was secured to the skull with three anchor screws and dental acrylic (Jet Acrylic Self Curing Resin and Liquid; Lang Dental Manufacturing Company, Inc., Wheeling, IL).
After surgery the rats were allowed to recover for 7 to 10 days while habituating to the sleep recording chambers. Habituation consisted of placing the rats in the recording chambers and connecting the electrode pedestal on the skull to a six-channel cable (363–441/six 80CM 6TCM, Plastics One) that led to amplifiers and a computer. Housing and sleep recordings occurred in a 12:12 hour light-dark cycle with transitions occurring at 8:00 a.m. and 8:00 p.m. States of sleep and wakefulness were recorded across 24 h in two 12-h, continuous segments that coincided with the light and dark cycle start times. The electrographic signals were amplified, filtered (electroencephalogram, 0.3–30 Hz; electromyogram, 10–100 Hz), and recorded at 128 Hz. After habituation, states of sleep and wakefulness were recorded for 24 h. For each 24 h digital recording, 10 s bins were scored as wakefulness, rapid eye movement (REM) sleep, or non-REM (NREM) sleep. During the recording sessions the rats could move freely and had ad libitum access to food and water.
A second group of HCR (n=6) and LCR (n=6) rats was used to phenotype mechanoreceptor thresholds by measuring paw withdrawal away from 2, 8, and 15 g of pressure caused by von Frey hairs applied to the bottom of a hind paw (Touch Test Sensory Evaluator Kit, Stoelting Co., Wood Dale, IL). As described previously44,45 these nylon hairs were slowly pushed against the skin until the hair bent. Each of the three hairs was applied five times in ascending order. Paw withdrawal was recorded as a positive response and the percent response to each von Frey hair was tabulated and averaged for each animal.
As described previously46, rats were conditioned daily to being placed in a Model 336T, IITC chamber for nociceptive testing (Life Science, Inc.; Woodland Hills, CA). The Hargreaves device made it possible to quantify the latency in seconds to paw withdrawal (PWL) away from onset a light beam focused on the hind paw.47 On the day of testing, animals were placed in the Hargreaves chamber and allowed to habituate for 60 min before obtaining measures of PWL. The light beam and an electronic timer were activated simultaneously. When the rat lifted its hind paw the heat source and the timer were stopped and the latency to paw withdrawal was recorded.46,48,49 Five measurements were obtained and averaged over 5 min of testing.
A unilateral chronic peripheral mononeuropathy50 of the sciatic nerve was created in adult male HCR (n=7) and LCR (n=7) rats. Prior to surgery, each rat was anesthetized with 3% isoflurane until breathing rate decreased to 60 breaths per min. After loss of wakefulness the rat was fitted with a Kopf Model 906 rat anesthesia mask and isoflurane concentration was lowered to 1.5% for the remainder of the procedure. Delivered isoflurane concentration and core body temperature were measured. The sciatic nerve was accessed via hind limb incision followed by blunt dissection of the biceps femoris. At a level proximal to its trifurcation, 5–8 mm of nerve were separated from tissue with minimal damage to surrounding muscle and tissue.50 Three polyglycolic acid sutures were placed around the sciatic nerve at 1 mm intervals from each other loosely enough to prevent complete ligation but tightly enough to induce a leg twitch response.50 The wound margin was sutured closed and rats were allowed six days to recover from surgery.
Thermal nociceptive testing was performed prior to and after the chronic constriction injury. A beam of light, which served as a noxious thermal stimulus, was directed through a glass floor and onto the plantar aspect of the hind paw. This light remained on until the rat withdrew its paw from the thermal stimulus. PWL was defined as the time (s) between commencement of the light beam and withdrawal of the hind paw.47 PWL was measured for all rats the day before sciatic nerve ligation and on days 7, 14, 21, 28, 35, and 42 after nerve ligation. During this six-week testing period, rats were conditioned in the testing chamber for 2 h daily. At the beginning of each testing day, rats were habituated to the chambers for 1 h before five PWL measurements were obtained with the Hargreaves method applied to the hind paws of both the operated and non-operated limb. To prevent tissue damage during nociceptive testing, the thermal light stimulus was set to automatically terminate (cut-off time) if there was no paw withdrawal after 18 s.
This study tested the one-tailed hypothesis that rats bred for low intrinsic aerobic capacity have enhanced nociception and disordered sleep. The 24-h recordings of sleep and wakefulness were scored for 138,240 epochs, each 10 s in duration. To avoid the problem of inflated degrees of freedom, the data were averaged for each of the 16 rats. Dependent measures included the percent of recording time spent in wakefulness, NREM sleep, and REM sleep; episode duration and number of episodes for each of the three states; and number of transitions between states. The data for percent of time spent in each state were normally distributed and fit the assumptions of two-way analysis of variance for repeated measures. The data describing recovery from chronic constriction nerve injury as a function of time were also analyzed using two-way analysis of variance for repeated measures. Post-hoc comparisons were made using Mann-Whitney and Bonferroni statistics. The von Frey data were not normally distributed and were analyzed using the Mann-Whitney statistic. Software used for statistical analyses included SAS v9.2 (SAS Institute Inc., Cary, NC), GBStat (Dynamic Microsystems, Inc., Silver Spring, MD) and Prism 5 (Graph Pad Software, Inc., La Jolla, CA).
Poincaré analyses are particularly useful for quantitatively evaluating the periodic nature of bi-stable rhythms such as the cardiac cycle,51 breathing,52,53 and sleep.54 Poincaré analyses were used in the present study to compare HCR and LCR animals for their ability to maintain stable episodes of REM sleep. Poincaré analysis made it possible to quantify two indices of variability. Short-term variability (SD1) expressed the variability in time from one REM sleep episode to the next REM sleep episode. Long-term variability (SD2) quantified the overall variability in duration of REM sleep epochs duration across the 24-h recording. Calculation of SD1 values for HCR and LCR rats was achieved with a four-step process: 1) The duration in s of each REM sleep interval was plotted (y) relative to (x) representing the duration of the previous REM sleep interval. 2) After all REM sleep epochs were plotted, the line of identity (x=y) was calculated and added to the Poincaré graph. 3) The Pythagorean theorem was used to calculate the perpendicular distance between each data point and the line of identity. 4) The standard deviation of these raw distances was calculated as the SD1 value for each HCR and each LCR rat, and these values were averaged across all HCR and LCR rats, respectively. SD2 values were obtained using step one above and then calculating the distance of each point from a line perpendicular to the line y=x and running through the mean duration of REM sleep intervals (i.e., the centroid of data points). As a final step, individual animal means of SD1 and SD2 for each HCR and LCR rat were used to evaluate rat strain differences by t-test. For all inferential statistics a P-value of less than 0.05 was considered significant.
Figure 2 illustrates the temporal distribution of sleep and waking states recorded across a continuous 24-h period for one representative HCR rat and one LCR rat. Figure 3 summarizes the average of eight different 24-h recordings for each strain and quantifies the strain-specific differences in sleep architecture. During the 24-h recordings LCR rats spent significantly (P<0.009) more time in wakefulness and significantly (P<0.01) less time in NREM sleep than HCR rats (fig. 3A). These differences were not apparent in the dark portion of the light:dark cycle (fig. 3B) and resulted predominantly from significant differences in wakefulness (P<0.007) and NREM sleep (P<0.005) that occurred during the light phase of the recordings (fig. 3C). HCR and LCR rats did not differ in the percent of recording time spent in REM sleep (fig. 3).
Figure 4 summarizes the variability in duration of REM sleep episodes characteristic of HCR and LCR animals. Comparison of the Poincaré distributions for the HCR (fig. 4A) and LCR (fig. 4B) rats indicates differences in the variability of REM sleep duration. Figure 4C illustrates the significantly (P<0.05) greater long-term variability in REM sleep episode duration characteristic of LCR rats. Short-term variability (SD1) in a Poincaré analysis quantifies the duration of one REM sleep episode (REMi) relative to the previous REM sleep episode (REMi-1). The differences in SD1 between HCR (fig. 4A) and LCR (fig. 4B) rats were not significant. Long-term variability (SD2) quantifies the variability in REM sleep episode duration as a function of rat strain. Figure 4C shows that SD2 was greater for LCR than HCR rats. Thus, LCR animals could initiate but not maintain stable episodes of REM sleep. Comparing the REM sleep data in figures 2, ,3,3, and and44 demonstrates how Poincaré analyses made it possible to quantify differences in the temporal organization of REM sleep.
The results of the Poincaré analyses encouraged a more detailed comparison of the temporal organization of sleep-wake states, and figure 5 summarizes those results. Averaging across 24 h, LCR animals had significantly (P<0.001) more transitions from wakefulness to NREM sleep and significantly (P<0.001) more transitions from NREM sleep to wakefulness than HCR rats (fig. 5A). Consistent with the figure 1 results, across the 24-h recordings LCR rats had a significantly (P <0.04) greater number of wakefulness episodes than HCR rats (fig. 5B). When LCR rats did have NREM sleep, the average duration of each NREM sleep episode was significantly (P<0.002) shorter than NREM sleep duration of HCR rats (fig. 5C).
There was no difference between HCR and LCR rats in mechano-sensory response as measured by von Frey test (fig. 6A). Power calculation indicated that 61 rats would be needed to demonstrate a difference in von Frey response at the P<0.05 level. As described previously,46 LCR rats revealed a modest but significantly shorter latency to paw withdrawal away from a thermal nociceptive stimulus (fig. 6B). Figure 6C shows the time course of PWL measured in HCR and LCR rats for one week before and for 42 days after chronic constriction injury of one sciatic nerve.50 Each of the seven points in figure 6C summarizes the mean and standard deviation latency in s of paw withdrawal away from a thermal stimulus to the hind paw. Before the peripheral neuropathy (pre-injury) there was no statistically significant difference in PWL between LCR and HCR animals. For the LCR rats, (fig. 6C) two-way ANOVA for repeated measures revealed a significant effect of peripheral neuropathy on PWL. Post-hoc test revealed significantly (P<0.05) enhanced nociception in LCR rats on days 7, 14, 21, and 28 after peripheral neuropathy. Measures of paw withdrawal in HCR rats (fig. 6C) revealed significantly (P<0.05) enhanced nociception for days 7 and 14 after chronic constriction injury of the sciatic nerve.
In 2000, the National Task Force on the Prevention and Treatment of Obesity reported delayed recognition of the fact that obesity is a significant health risk.55 Although relevance of obesity for anesthesiology was noted in 1975,56 only recently has the interaction between obesity, sleep, and pain become apparent.3,5,37,57 Obesity has replaced smoking as a major disease burden58 and projection data indicate that by 2020, half of all Americans may be obese.59 The results are discussed relative to emerging evidence that obesity is associated with disordered sleep, which can cause hyperalgesia and increase opioid requirement for effective pain management.
The data from rats bred for low intrinsic aerobic capacity are consistent with human data documenting a relationship between metabolic syndrome, sleep, and nociception. For example, humans with poor physical fitness and a high body mass index exhibit disrupted and diminished sleep compared to those with a normal body mass index.18,20,60 Humans with metabolic syndrome and type II diabetes spend more time in bed and less time asleep.12,13,16,17
Human data also support the view that reduced sleep leads to increased body mass and decreased fitness by way of increasing cortisol and interleukin-6, increasing ghrelin, and decreasing leptin.17–19 Thus, shortened sleep has been associated with decreased fitness and the present results show for the first time that diminished aerobic fitness in LCR rats is characterized by disordered sleep. Low intrinsic aerobic capacity was associated with decreased NREM sleep time and increased time awake (figs. 2 and and3).3). Sleep disruption in rats with low aerobic capacity also was characterized by greater variability in duration of REM sleep (fig. 4) and more transitions between wakefulness and NREM sleep (fig. 5) compared to rats bred for high intrinsic aerobic capacity. The decreased amount of sleep and inability to maintain sleep characterizing this rodent model of metabolic syndrome31,32,61 resemble features of human insomnia. In support of the potential clinical relevance of this rodent model, disordered sleep and short sleep duration characteristic of human insomnia are risk factors for type II diabetes.62 The present results encourage future studies designed to obtain long term recordings of sleep and wakefulness from HCR and LCR rats.
Obesity and insulin resistance,63–65 specific features of metabolic syndrome, are associated with painful, idiopathic neuropathy,23 enhanced nociception,66,67 and disordered sleep.68–71 Although data clearly document an association between metabolic syndrome and pain, no previous studies have characterized the effect of metabolic syndrome on the resolution of experimentally imposed, chronic pain. Compared to HCR rats, the LCR phenotype revealed a delayed recovery from chronic peripheral mononeuropathy (fig. 6C). The fig. 6C results, and the fact that HCR and LCR rats have been bred for the intrinsic (i.e., untrained) component of aerobic capacity, implies that genetic and metabolic factors altered the resolution of the neuropathy. This implication fits with the finding that human obesity is associated with increased hospital admissions and longer hospital stays.72 The disordered sleep characteristic of LCR rats may also contribute to hyperalgesia. In normal, pain-free humans sleep loss causes hyperalgesia25,28 and non-restorative sleep impacts pain management.73 Opioids disrupt NREM sleep and inhibit the REM phase of sleep38 and REM sleep disruption consistently has been shown to diminish the analgesic properties of opioids.74
There is good precedent for animal models contributing to clinical anesthesiology. Rodent studies have provided the background for spinal drug administration now routine in clinical care,75 porcine models helped elucidate the mechanisms of malignant hyperthermia,76 and unique features of goat brain vasculature helped differentiate brain versus spinal cord sites of anesthetic action.77 All models have a limited domain of applicability and the strengths and limitations of the LCR and HCR rats have been described in detail.61 A known limitation of sensory threshold testing is that the data are characterized by a high degree of variability.78,79 This variability may contribute to the lack of rat strain-specific difference in response to von Frey testing (fig. 6A), as well as differences between HCR and LCR rats during acute nociceptive testing (fig. 6B) but not during pre-injury nociceptive testing (fig. 6C). Likewise, the complexity of animal models of nociception is recognized80 and future nociceptive testing should include additional pain models and sensory modalities.
The polygenic nature of complex diseases emphasizes the advantages of models created by the selective breeding for naturally occurring traits over transgenic models that manipulate a single gene or gene product.61 This advantage is particularly clear for efforts to model hypertension, metabolic syndrome, and disordered sleep, all of which complicate anesthesia care. The potential for LCR and HCR rats to provide a unique resource for anesthesiology research is supported by evidence emphasizing the biological centrality of oxygen uptake and delivery61 and the special relevance of oxygen for anesthesiology.81
The present findings suggest homology between obese human and rat for the traits of sleep fragmentation and nociception, and support the interpretation that LCR rats develop some features of metabolic syndrome.32 Sleep apnea is the second most common sleep disorder and a potential problem for anesthesia care.82 This is consistent with evidence that obstructive sleep apnea, similar to metabolic syndrome, is a systemic disease.83 The present results encourage future studies using whole body plethysmography53 to characterize the actions of intravenous and volatile anesthetics on the respiratory control of LCR and HCR rats. In view of the fact that adenosine is antinociceptive84,85 and that exercise increases brain adenosine,86 future studies also will determine the extent to which adenosinergic neurotransmission87 is one mechanism through which intrinsic aerobic capacity modulates sleep and nociception.
For expert assistance the authors thank Sha Jiang, B.S. (Research Associate), Mary A. Norat, B.S. (Senior Research Associate), Sarah L. Watson, B.S. (Senior Research Associate) and Elizabeth Gauthier, B.S. (Research Assistant) from the Department of Anesthesiology, University of Michigan, Ann Arbor, MI, and Kathy Welch, M.A., M.P.H. (Center for Statistical Consultation and Research, University of Michigan). Lori Gilligan, L.V.T (Animal Technician Senior) and Nathan Kanner, B.A. (Senior Research Laboratory Technician) from the Department of Anesthesiology, provided expert care of the rat colony.
Support: Supported by grants HL40881, HL65272 (RL), MH45361 (HAB), and NCRR R17718 (LGK and SLB) from the National Institutes of Health, Bethesda, MD, and by the Department of Anesthesiology, University of Michigan, Ann Arbor, MI
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Conflicts of Interest Ralph Lydic and Helen A. Baghdoyan received past support from Sepracor Pharmaceutical (Marlborough, Massachusetts) for studies of the effects of eszopiclone on acetylcholine release in rat brain stem.
Meetings at which work was presented: Abstracts presented at the Experimental Biology Meeting, San Diego, CA, April 7, 2008; and Association of Professional Sleep Societies Meeting, Baltimore, MD, June 7, 2008.
Summary Statement: Rats selectively bred for low intrinsic aerobic capacity develop metabolic syndrome and have phenotypes of disordered sleep and enhanced nociception that are homologous to traits of obese humans.