Physiological basis and pharmacology of motion sickness: an update

Abstract

Motion sickness can occur when sensory inputs regarding body position in space are contradictory or are different from those predicted from experience. Signals from the vestibular system are essential for triggering motion sickness. The evolutionary significance of this malady is unclear, although it may simply represent the aberrant activation of vestibuloautonomic pathways that typically subserve homeostasis. The neural pathways that produce nausea and vomiting during motion sickness are presumed to be similar to those that generate illness after ingestion of toxins. The neural substrate of nausea is unknown but may include neurons in the hypothalamus and inferior frontal gyrus of the cerebral cortex. The principal motor act of vomiting is accomplished through the simultaneous contractions of inspiratory and expiratory respiratory muscles and is mediated by neurons in the lateral medullary reticular formation and perhaps by cells near the medullary midline. Cocontraction of the diaphragm and abdominal muscles increases pressure on the stomach, which causes gastric contents to be ejected through the mouth. Effective drugs for combating motion sickness include antihistamines, antimuscarinics, 5-HT_1A (serotonergic) receptor agonists and neurokinin type 1 receptor antagonists. However, considerable information concerning the physiological basis and pharmacology of motion sickness is unknown; future research using animal models will be required to understand this condition.

Introduction

Motion sickness is a malady characterized by a combination of signs and symptoms that accompany movement or perceived movement in the environment. This disorder has been of interest to many investigators and has been described in several previous reviews [e.g., 30, 94, 110, 113, 126]. Many different circumstances can elicit motion sickness, including travel in automobiles, aircraft, spacecraft and boats and exposure to moving visual scenes [see 110, 113, 125 for reviews]. All these conditions are similar in that multiple sensory cues concerning body position in space are available and possibly can provide contradictory information. Reason and Brand [126] argued that “situations which produce motion sickness are all characterized by a condition of sensory rearrangement in which motion information signaled by the vestibular receptors, the eyes, and non-vestibular proprioceptors, are at variance with the kinds of inputs that are expected on the basis of past experience.” Subsequent studies have supported this idea that “sensory conflict” may lead to space sickness [121] and motion sickness that occurs on Earth [see 94, 113 for reviews]. Even “simulator sickness” [61] and other types of motion sickness triggered by exposure to a moving visual environment can be due to sensory conflict, because these situations are accompanied by vestibular cues that indicate the head is stable in space (despite the fact that visual cues indicate the head is moving) 122, 161.

However, the sensory conflict theory does not readily explain motion sickness produced by all conditions. For example, it is not clear why passive low-frequency vertical linear acceleration should be nauseogenic in human subjects [122]. This apparent contradiction to the sensory conflict theory may be explained by the recent discovery that sensory inputs other than those traditionally thought to trigger motion sickness are involved in producing this malady. For example, Mittelstaedt introduced evidence to suggest that inputs from visceral graviceptors contribute to the determination of body position is space [see 108, 109 for reviews]. If a mismatch between the visceral “body position signal” and vestibular signals was present, then the resulting sensory conflict could theoretically induce motion sickness during vertical motion [145]. Further research will be required to determine whether the sensory conflict theory adequately explains the occurrence of all forms of motion sickness.

The most critical signals required for the generation of motion sickness come from the vestibular system, as evidenced by the fact that individuals with bilateral vestibular dysfunction are not susceptible to motion sickness induced by stimuli that are typically provocative 23, 125. The peripheral vestibular system is located in the inner ear, in a structure referred to as the labyrinth, as discussed in many previous reviews [e.g., 42, 127, 154]. Two types of end organs are present in the periphery: semicircular canals and otolith organs. Both end organs contain the same type of receptor: the hair cell, which synapses on afferents of the VIIIth cranial nerve. The three semicircular canals in each inner ear are roughly located at right angles to each other, which permits detection of head movements (rotational acceleration) in any direction. The sensory receptors within the semicircular canals respond to angular acceleration, which occurs when the head is rotated or when the entire head and body is turned, as on an amusement ride that spins. Angular head movements produce a change in the discharge pattern of afferents innervating at least two of the six semicircular canals on the two sides of the head; the degree to which different canal afferents are affected depends on the direction and intensity of the movement. In contrast, the two otolith organs, the utriculus and the sacculus, provide information about the static position of the head in space (head position with respect to gravity) and about linear accelerations placed on the head (as during falling or when accelerating in a car). Otolith organ hair cells have many different orientations, and the two otolith organs are positioned perpendicular to each other, which allows detection of linear accelerations and head tilts in many different planes. The central nervous system can decipher the position of the head in space by analyzing the pattern of otolith organ afferent discharges. A number of neurotransmitters and neuromodulators influence the activity of vestibular nucleus neurons, including acetylcholine, glutamate, glycine, GABA, histamine, norepinephrine, dopamine, serotonin, substance P, somatostatin, adrenocorticotropic hormone [ACTH] and enkephalin [see 6, 33, 172 for reviews]. Thus, a large variety of pharmacological agents could potentially affect the occurrence of motion sickness through their actions in the vestibular nuclei.

The most prominent indicators of motion sickness in humans include nausea and vomiting, pallor, cold sweating and a large increase of plasma levels of arginine vasopressin 63, 110, 113, 126. Money et al. [113] proposed that these responses fall into two categories: those related to emptying the stomach and those related to “stress” that may be secondary to stomach emptying. The delivery of appropriate motion stimuli in certain animal models can also trigger similar physiological effects, including vomiting and an elevation of plasma vasopressin levels [40]. Animal models commonly used for the study of motion sickness-induced emesis include the cat and Suncus murinus, a species of insectivora [137]; a few studies have also used Bolivian squirrel monkeys. The dog has been largely abandoned as an animal model for motion sickness because the drugs that diminish motion-related emesis in this species differ from those in other animals (see Pharmacology of Motion Sickness below). It is not clear whether another animal commonly used for emetic research, the ferret, will be useful for studies on motion sickness. However, many species, including rodents and rabbits, lack the ability to vomit [13] and thus are unable to exhibit the most obvious indicator of motion sickness. Furthermore, administration of at least some toxins to rodents does not result in a large increase in plasma levels of vasopressin, although plasma oxytocin levels increase substantially 140, 141, 142. The functional significance of the oxytocin release is not clear, but it appears that this hormone may be an indicator of “nausea” in rodents 140, 141, 142. Other possible correlates of nausea in nonemetic animals may include the production of conditioned taste aversions and the ingestion of nonnutritive substances such as pica 107, 152. Conflicting motion stimuli have been shown to induce eating of clay in rodents [90], although this response may not have sufficient temporal linkage with the onset of motion sickness to be a sensitive indicator of this condition. Further research is required to determine whether the assay of blood oxytocin levels can be used to index the severity of motion sickness in nonemetic animals.