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Koglin and Kayser Extreme Physiology & Medicine 2013, 2:1 http://www.extremephysiolmed.com/content/2/1/1 RESEARCH Open Access Control and sensation of breathing during cycling exercise in hypoxia under naloxone: a randomised controlled crossover trial Laurent Koglin1 and Bengt Kayser2* Abstract Background: Opioid receptors are possibly involved in the perception of exertion and the ventilatory response to exercise. We compared incremental cycling exercise in conditions of normoxia and hypoxia (11% O2) after injection of the opioid receptor antagonist naloxone (30 mg i.v.) or placebo. Naloxone was expected to increase sensation of breathing and cycling and to curtail exercise performance more in hypoxia. Methods: Ten healthy subjects (29 ± 2 years, 183 ± 6 cm, 75 ± 7 kg, mean ± SD) cycled in normoxia and hypoxia until voluntary exhaustion, receiving naloxone or placebo in a balanced double-blind crossover design. Results: Hypoxia decreased peak power output by 37%–39% with placebo and naloxone (P < 0.001, no effect of naloxone). Switching to normoxia at exhaustion in hypoxia allowed continuing up to 97%–100% of power developed in normoxia with placebo and naloxone (P < 0.001, no effect of naloxone). Perceived exertion increased in hypoxia, dropped upon switching to normoxia and increased again towards exhaustion, no effect of naloxone. SpO2 (earlobe oximetry) was lower in hypoxia, dropping to 64%–68% with naloxone and placebo. The ventilatory response to exercise in normoxia and hypoxia was not changed by naloxone. Conclusions: It follows that in healthy subjects the ventilatory response and the perception of exertion in hypoxia as compared to normoxia do not involve the endogenous opioid system, and the latter does not play a role in limiting maximum exercise capacity in hypoxia. Keywords: Altitude, Exercise, Human, Opioid, Hypoxia Background afferent sensory information [5]. Sgherza et al. [9] found In both healthy subjects and patients, dyspnoea and leg that in normoxia, in healthy trained subjects, naloxone fatigue are the main symptoms limiting exercise capacity compared to placebo decreased incremental exercise [1-4]. Dyspnoea is accompanied by activation of cortico- performance and suggested that sensation of exertion is limbic structures implicated in interoceptive awareness under influence of endogenous opioids and may be a and nociceptive sensations, such as pain, and involves limiting factor for maximum aerobic exercise capacity. the opioid system [5]. In patients with dyspnoea, Acute hypoxia is a potent stressor, especially when exogenous opioids can alleviate breathing-related dis- combined with an exercise challenge, changing the per- comfort and improve exercise performance [5-8], while ceived level of exertion [10]. Acute exposure to hypoxia injection of naloxone hydrochloride, a non-specific increases ventilation and cardiac output in order to min- opioid antagonist that crosses the blood–brain barrier, imise the reduction in arterial oxygen content and sys- can decrease performance [5]. Opioids can relieve dys- temic mass oxygen transport. Despite these acute pnoea by altering central processing of efferent and adaptations, incremental exercise testing in such condi- tions (e.g. an FiO2 equivalent to an altitude of 5,000 m or higher, hereafter referred to as severe hypoxia) invari- * Correspondence: [email protected] 2Institute of Movement Sciences and Sports Medicine, Faculty of medicine, ably results in compromised aerobic exercise capacity. University of Geneva, 10, rue du Conseil Général, Genève 4 1205, Switzerland The mechanisms behind this limitation of exercise Full list of author information is available at the end of the article © 2013 Koglin and Kayser; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Koglin and Kayser Extreme Physiology & Medicine 2013, 2:1 Page 2 of 10 http://www.extremephysiolmed.com/content/2/1/1 capacity in hypoxia are still poorly understood [11-13]. tests, the subjects came to the lab on four different occa- A puzzling observation is that despite maximum effort sions at least 24 h apart to perform incremental cycling in severe hypoxia, cardiac output remains submaximal, exercise until voluntary exhaustion, twice in normoxia suggesting early motor drive withdrawal [11,12]. How- and twice in acute normobaric hypoxia (FIO2 = 10.65% ever, while the locomotor muscles are not driven as hard O2, in Geneva the equivalent of an altitude of approxi- during large muscle volume effort in such conditions, mately 5,000 m). The subjects cycled at 80 rpm on a the contrary is the case for the respiratory muscles. mechanically braked ergometer (Monark 282E, Varberg, Ventilation is higher for any given level of oxygen con- Sweden). After 3 min of resting baseline measurements, sumption during exercise in hypoxia, as compared to the subjects would warm up at 40 watt for 3 min. In normoxia, and is accompanied by a concomitant in- order to obtain similar durations of exercise times be- crease in the sensation of breathing effort [10]. Since tween subjects and between conditions of normoxia and blocking the effect of endogenous opioids on the sensa- hypoxia, the duration of steps was adapted between con- tion of exertion can increase symptom intensity and cur- ditions and stages. After warm-up, the subjects incre- tail performance in normoxia [9], it is possible that such mented by 3-min steps of 40 up to 200 watt in normoxia an effect would be exacerbated in hypoxia. We therefore and then by 20 watt up to voluntary exhaustion, while in hypothesised that blocking opioid receptors may de- hypoxia, they incremented by 40 up to 120 watt and crease aerobic exercise performance more in hypoxia then by 20 watt up to voluntary exhaustion. When than in normoxia. To test this hypothesis, we compared reaching exhaustion in hypoxia, the subjects were incremental cycling exercise in conditions of normoxia and switched to room air (‘normoxia switch’) and strongly hypoxia (11% O2) after injection of the opioid antagonist encouraged to continue cycling while the load was naloxone in comparison to a placebo. Our expecta- increased by 20 watt every 90 s until reaching secondary tions were that under naloxone the sensation of voluntary exhaustion. breathing effort and that of cycling would increase and curtail exercise performance more in hypoxia as compared to normoxia. Intervention In each condition, they did this once after immediate Methods pre-exercise intravenous injection of naloxone (30 mg Subjects naloxone HCl in 30 ml saline) and once after placebo Thirteen healthy trained men volunteered to participate (30 ml saline). The conditions normoxia and hypoxia in the study. Inclusion criteria were an age between 18 were in a randomised order. Naloxone and placebo were and 30 years and >4 h/week of endurance training. Ex- administered in a balanced double-blind crossover de- clusion criteria were presence of any relevant chronic or sign. The research support section of the Geneva Univer- acute disease, having done a maximal capacity training sity Hospitals pharmacy prepared the vials, the numbering or a race during the last 48 h, symptoms/signs of viral scheme and the randomization envelopes and released the illness in the week preceding the experiments or expos- randomization key after data analysis was completed. The ure to altitude in the 2 months before the study. The subjects started exercising within 5 min after injection and study was approved by the research ethics commission of reached exhaustion within 30 min, approximately one half the Geneva University Hospitals and SwissMedic and com- oftheserumhalf-lifeofnaloxonereportedinhumans[14]. plied with the principles of the Declaration of Helsinki. All subjects were screened by a physician, were fully informed of the nature and risks of the experiments, knew of their Normoxia and hypoxia right to withdraw at any time and signed an informed Normobaric hypoxia was obtained by mixing N2 into consent form. ambient air under control of FIO2 (Altitrainer, SMTec, Nyon, Switzerland). The gas-mixing system was attached Exercise protocol via a piece of large-bore low-resistance tubing to the in- After inclusion, the subjects first performed two habitu- spiratory valve of a low-resistance three-way valve (Hans ation experiments, identical to the real experiments ex- Rudolph 2700, Shawnee, KS, USA) mounted in series cept for the injection, to get used to the equipment and with a turbine flow measurement set-up (Vmax 29c, to experience cycling in acute hypoxia. They were Sensormedics, Loma Linda, CA, USA) attached to a instructed not to do any heavy training on the days pre- tightly fitted face mask (Hans Rudolph). The subjects al- ceding the experiments and to refrain from caffeine in ways breathed through the same set-up, also in nor- the 4 h preceding a test. To control for circadian moxia. The gas-mixing device was set to room air for rhythm, for a given subject, all experiments were per- the normoxia experiments and to a simulated altitude of formed at similar times of the day. After the habituation 5,000 m for the hypoxia experiments. Koglin and Kayser Extreme Physiology & Medicine 2013, 2:1 Page 3 of 10 http://www.extremephysiolmed.com/content/2/1/1 Material and measurements Chicago, IL, USA). Repeated measures ANOVA was used Gas exchange and breathing parameters were measured to test for within-group effects across time. Following sig- breath-by-breath with a metabolic cart (Vmax 29c, nificant main effects, planned pairwise comparisons were Sensormedics). Prior to each experiment, the system was made using Holm's sequential Bonferroni procedure. calibrated with a 3-L syringe and gas mixtures of known Results are expressed as mean ± SD. Statistical signifi- composition. Heart rate was measured by telemetry with cance was set at P<0.05. a thoracic belt (Polar, Tampere, Finland).

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