Effects of Motion Sickness on Human Thermoregulatory Mechanisms Gerard Nobel Thesis for doctoral degree (Ph.D.) Department of Environmental Physiology School of Technology and Health KTH (Royal Institute of Technology) Academic dissertation which, with permission from KTH (Royal Institute of Technology) Stockholm, will be presented on Friday December 10, 2010, at 13.30, in lecture hall 3-221, Alfred Nobels allé 10, Huddinge, Sweden. TRITA-STH Report 2010:6 ISSN: 1653-3836 ISRN: ISRN KTH/STH/2010:6--SE ISBN: 978-91-7415-795-6 © Gerard Nobel, Stockholm 2010 Cover photo: KODIAK, Alaska - A life raft from the fishing vessel Alaska Ranger floats in the Bering Sea after the survivors were rescued by the Coast Guard. Photo by PA3 Richard Brahm, US Coast Guard. Note that these types of life rafts are notorious for causing motion sickness. “Seasickness: at first you are so sick you are afraid you will die, and then you are so sick you are afraid you won't die.” Allegedly by Mark Twain. Abstract The presented studies were performed to investigate the effects of motion sickness (MS) on human autonomic and behavioural thermoregulatory mechanisms during cold stress and in a thermoneutral environment. The roles of histaminergic and cholinergic neuron systems in autonomic thermoregulation and MS-dependent dysfunction of autonomic thermoregulation were studied using a histamine-receptor blocker, dimenhydrinate (DMH), and a muscarine-receptor blocker, scopolamine (Scop). In addition, the effects of these substances on MS-induced nausea and perceptual thermoregulatory responses were studied. MS was found to lower core temperature, during cold stress by attenuation of cold-induced vasoconstriction and decreased shivering thermogenesis, and in a thermoneutral environment by inducing sweating and vasodilatation. The increased core cooling during cold stress was counteracted by DMH but not by Scop. In a thermoneutral environment, the temperature was perceived as uncomfortably warm during and after the MS provocation despite decreases in both core and skin temperature. No such effect was seen during cold- water immersion. Both pharmacologic substances had per se different effects on autonomic thermoregulatory responses during cold stress. Scop decreased heat preservation, but did not affect core cooling, while DMH reduced the rate of core cooling through increased shivering thermogenesis. Both DMH and Scop per se decreased thermal discomfort during cold- water immersion. Findings support the notion of modulating roles of histamine (H) and acetylcholine (Ach) in autonomic thermoregulation and during MS. MS activates cholinergic and histaminergic pathways, thereby increasing the levels of H and Ach in several neuro-anatomical structures. As a secondary effect, MS also elevates blood levels of several neuropeptides, which in turn would influence central and/or peripheral thermoregulatory responses. In conclusion, MS may predispose to hypothermia, by impairment of autonomic thermoregulation in both cold and thermoneutral environments and by modulation of behavioural thermoregulatory input signals. This might have significant implications for survival in maritime accidents. Keywords: motion sickness, autonomic thermoregulation, behavioural thermoregulation, hypothermia, acetylcholine, histamine. i List of publications The thesis is based on the following papers, which are referred to by their Roman numerals (I-IV). I. G. Nobel, A. Tribukait, I.B. Mekjavic and O. Eiken, Effects of motion sickness on thermoregulatory responses in a thermoneutral air environment (in manuscript). II. G. Nobel, O. Eiken, A. Tribukait, R. Kölegård and I.B. Mekjavic, Motion sickness increases the risk of accidental hypothermia , Eur J Appl Physiol 98 (2006) 48-55. III. A. Tribukait, G. Nobel, I.B. Mekjavic and O. Eiken , Effects of anti- histaminic and anti-cholinergic substances on human thermoregulation during cold provocation , Brain Res Bull 81 (2010) 100-106. IV. G. Nobel, A. Tribukait, I.B. Mekjavic and O. Eiken, Histaminergic and cholinergic neuron systems in the impairment of human thermoregulation during motion sickness , Brain Res Bull 82 (2010) 193-200. Publications protected by copyrights are reproduced with permission from the publishers. ii Table of contents Abstract ……………………………………………………………………….............. i List of publications …………………………………………………………………… ii Table of contents …………………………………………………………………….. iii Abbreviations ………………………………………………………………………... v Introduction ………………………………………………………………………….. 1 Aims …………………………………………………………………………………… 3 Methods and experimental procedures ……………………………………………... 4 Subjects……………………………………………………………………………. 4 Motion Sickness provocation……………………………………………………… 4 Cold provocation and passive rewarming…………………………………………. 5 Temperature perception and thermal comfort…………………………………….. 5 Body temperatures………………………………………………………………… 5 Cardiovascular variables…………………………………………………………... 5 Mean Arterial Pressure and Heart Rate …………………………………….… 5 Forearm vs. fingertip temperature difference …………………………………. 6 Respiratory variables……………………………………………………………… 6 Sweating rate………………………………………………………………………. 6 Recording techniques……………………………………………………………… 6 Analysis of data…………………………………………………………………… 7 Experimental protocols……………………………………………………………. 8 Methodological considerations……………………………………………………. 9 Results ………………………………………………………………………………… 10 MS ratings…………………………………………………………………………. 10 Effect of MS and anti-MS drugs on core temperature…………………………….. 10 Effect of MS and anti-MS drugs on peripheral vasomotor tone…………………... 12 Effect of MS and anti-MS drugs on skin temperature…………………………….. 13 Effect of MS and anti-MS drugs on shivering…………………………………….. 14 Effect of MS and anti-MS drugs on sweating rate………………………………… 15 Effect of MS and anti-MS drugs on Tp and Tc…………………………………… 16 Discussion ……………………………………………………………………………... 19 Motion Sickness…………………………………………………………………… 20 Adrenocorticotropic hormone (ACTH) in MS ………………………………… 21 Arginine vasopressin (AVP) in MS ……………………………………………. 21 Vasoactive intestinal polypeptide (VIP) in MS ………………………………... 21 iii Conclusions on MS ……………………………………………………………. 21 Thermoregulation………………………………………………………………….. 23 Autonomic thermoregulation .............................................................................. 23 Neural organization and pharmacology of thermoregulation ............................ 23 Thermoregulation, central effects of Histamine ………………………………. 23 Thermoregulation, central effect of Acetylcholine …………………………….. 23 Behavioural thermoregulation ………………………………………………... 24 Conclusions on thermoregulation ……………………………………………... 24 MS and thermoregulation…………………………………………………………. 24 Neuropharmacological links between MS and thermoregulation…………….. 24 Vasomotor tone ………………………………………………………………... 25 Shivering ………………………………………………………………………. 26 Sweating ……………………………………………………………………….. 27 Effects of MS on behavioural thermoregulation/thermal perception …………. 28 Conclusions on MS and thermoregulation ……………………………………. 28 Practical implications……………………………………………………………… 29 Summary and conclusions …………………………………………………………… 32 Acknowledgements …………………………………………………………………... 34 References …………………………………………………………………………….. 35 Publications: I-IV iv Abbreviations Ach Acetylcholine ACTH Adrenocorticotropic hormone AVP Arginine vasopressin CN Control DMH Dimenhydrinate H Histamine/Histaminic H1R Histamine-1 receptor M Muscarine/Muscarinic MS Motion sickness MS-CN Notion sickness control MS-DMH Motion sickness dimenhydrinate MS-P Motion sickness placebo MS-Scop Motion sickness scopolamine MSR Motion sickness rating POAH Preoptic anterior hypothalamus PVN Paraventricular nucleus Scop Scopolamine SWR Sweating rate SON Supraoptic nucleus Tc Thermal comfort TEMPSC Totally enclosed motor propelled survival craft TMN Tuberomammillary nucleus Tp Temperature perception VIP Vasoactive intestinal peptide v Introduction Working in a maritime environment means that one is exposed to the elements of nature, which, in extreme conditions, may imply grave risks. The present work investigated thermoregulatory responses to a combination of two conditions related to the maritime environment: cold stress, by means of cold-water immersion, and motion sickness (MS) provocation, by means of cross-coupled Coriolis stimulation. There is a distinct difference between the risks associated with the two conditions. While cold stress obviously may have serious consequences in terms of hypothermia, MS is often regarded as a mere nuisance, which, in severe cases, may result in incapacitation. At the outset of these studies, information was scanty as to how MS might impinge on thermoregulation. In the 19th century, the German physician Hesse [63] was one of the first to report a decreased body temperature in relation to MS. He noticed that sea sick passengers on a transatlantic voyage showed a lowered rectal temperature. Temperatures returned to normal levels concomitant with the abatement of MS symptoms, suggesting a causal relationship [63]. Hemmingway (1944) [62], Crampton (1955) [32] and Graybiel (1969) [52] also found a decrement in core temperature during or after MS provocation. These effects were however not discussed [52], or where attributed to either an increased heat loss due to both increased ventilation and evaporative heat loss [32], or to increased convective heat loss associated with the experimental procedures [62]. The question whether MS might influence survival during maritime accidents was raised by Keatinge [74] in 1965 and by Golden [45] in 1973, the latter reporting on