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This experimentation partially defines, for the first time, the response of beta-endorphin (ENDO) in man during tests designed to elicit nausea and motion sickness. These responses are similar to those associated with arginine vasopressin (AVP) and adreno-corticotropin (ACTH) to the extent that all hormones rise in response to motion sickness (p less than 0.003). Repeated exposure diminished motion-induced release of ENDO (p less than 0.005) and AVP (p less than 0.004) despite a three-fold increase in resistance to motion stimuli. Higher post-stress levels of AVP (p less than 0.04) and ACTH (p less than 0.02) were correlated with greater resistance to motion sickness. These data support the hypothesis that release of AVP is a significant link between stressful motion and motion-induced nausea and other autonomic system changes. Further, resistant individual apparently can tolerate higher peripheral levels of AVP before nausea results. Peripheral release of ENDO and ACTH may follow release of AVP; however, given the extensive and complex functional interactions that exist between AVP and the opiate systems, it is not yet possible to define a clear role for ENDO in the etiology of motion sickness.

Three fundamental approaches used in the selection of new agents for the evaluation in the prevention of space-motion sickness (SMS) are reviewed, with emphasis on drugs under investigation at the Johnson Space Center. These approaches are: (1) the selection of agents from drug classes that possess pharmacologic properties of established antimotion sickness agents, (2) the selection of drugs that are used to prevent emesis caused by means other than the exposure to motion, and (3) basic research that characterizes individual differences in susceptibility to SMS. In the latter type of studies, it was found that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistance. The review details the experimental data collected on AVP and adrenocorticotropin. It is noted that data support interrelated roles for AVP and opioid peptides in SMS.

Terfenadine (Seldane) was admisistered to 14 male subjects in a randomized, double-blinded, and cross-over design to assess the efficacy of this peripherally active antihistamine as an antimotion sickness drug. Terfenadine possesses practically no central side effects. A staircase profile test was administered 4 h following placebo or a single oral dose of terfenadine (300 mg). The study revealed a statistically significant therapeutic effect from terfenadine (p less than 0.05). This led to a conclusion that, because the drug does not or only poorly crosses the blood-brain barrier, a selective peripheral antihistamine action may be sufficient in the control of motion sickness induced through cross-coupled accelerative semicircular canal stimulation using a rotating chair. This finding implies that other peripherally acting agents might be found that possess even greater antimotion sickness efficacy. The present research raises additional questions regarding current theories on the etiology of motion sickness, its associated autonomic system dysfunction, and the validity of assumptions that effective pharmacological agents must act centrally.

Data related to the mechanism responsible for the antimotion sickness effects of psychostimulants such as amphetamine are examined. From the analysis of current literature and new evidence, the following three hypotheses are suggested: (1) selective enhancement of dopaminergic, but not noradrenergic, transmission is sufficient to account for amphetamine-induced resistance and, perhaps, for natural resistance to motion sickness; (2) the site of this enhanced dopaminergic transmission is probably within the basal ganglia; and (3) the neuropharmacology of the basal ganglia, but not of the brain-stem vestibular areas, can account for the therapeutic synergism of scopolamine and amphetamine. The therapeutic action of psychostimulants may be dissociable from some of their side effects, particularly cardiovascular effects related to peripheral norepinephrine release.

Astemizole was orally administered to 20 subjects in a randomized, double-blind design to assess the efficacy of this peripherally active antihistamine as an antimotion sickness drug possessing no central side-effects. Measures of vestibular ocular reflex (VOR) were made to evaluate the agent as a selective vestibular depressant. Following one week of orally administered astemizole (30 mg daily), a Staircase Profile Test, a VOR test, and a variety of tests of cognitive performance were administered. These tests revealed no statistically significant effects of astemizole. This leads to the conclusion that, although the drug probably reaches the peripheral vestibular apparatus in man by crossing the blood-vestibular barrier, a selective peripheral antihistamine (H1) action is inadequate to control motion sickness induced through cross-coupled accelerative semicircular canal stimulation in a rotating chair.

The concentrations of adrenocorticotropic hormone (ACTH), vasopressin (AVP), epinephrine (EPI), and norepinephrine (NE) in 22 subjects administered 10 to 20 mg of metoclopramide prior to parabolic flight are measured. The effect of metoclopramide on motion sickness is examined. It is observed that metoclopramide is ineffective in the modulation of motion sickness due to stressful linear and angular acceleration and orbital flight, and it does not affect serum hormones prior to parabolic flight. It is detected that the serum level of AVP declines following emesis induced by parabolic flight and stressful angular acceleration; the serum levels of ACTH and EPI are elevated by parabolic flight and stressful angular acceleration; and serum NE is significantly elevated immediately following emesis. The possible roles of these hormones in the etiology of space motion sickness are discussed.

Orally administered metoclopramide (REGLAN) at doses of 10 or 20 mg, 75 min prior to either stressful linear acceleration (parabolic flight) or cross-coupled accelerative semicircular canal stimulation in a rotating chair was evaluated for its ability to prevent emesis or nausea II, respectively. Although metoclopramide is an effective antiemetic agent that enhances gastric emptying and prevents cancer chemotherapy-induced emesis, it was not possible to demonstrate any significant (p less than 0.05) effects of this drug on motion sickness.

Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, the efficacy of dexamethasone and metyrapone is tested in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80 percent more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.