Motion sickness: a modulatory role for the central cholinergic nervous system.

The present review has extended the general theory of motion sickness proposed by Wood and Graybiel [135, 136] by identifying specific neurophysiological mechanisms that are involved in motion sickness and by interpreting the actions of both scopolamine and amphetamine as effective anti-motion sickness drugs within this neurophysiological context. The neurochemical and neurophysiological effects of scopolamine have been reviewed in relationship to central cholinergic pathways. Cholinergic pathways have been associated with both the perception and expression of normal and excessive levels of motion stimuli. New approaches to the problem of the prevention of motion sickness have been considered. Efferent nicotinic innervation at the primary sensory hair cells and the medial vestibular nucleus were identified as sites where modulation by cholinergic drugs might exert a beneficial influence. However, it was generally conceded that the complexity of the cholinergic system and the interaction of scopolamine with that system left open the possibility that pharmacological doses of drugs specific to the cholinergic system might exert significant modulatory influences at alternative sites, as well.

New pharmacologic approaches to the prevention of space/motion sickness.

Fundamental approaches in selection of new agents for evaluation in prevention of space/motion sickness (SMS) are reviewed. The discussion centers on drugs under investigation at the Johnson Space Center. Methodology that employs the rotating chair for measuring SMS symptomatology and susceptibility is described. The most obvious approach to the development of new agents relies on selection of agents from drug classes that possess pharmacologic properties of established anti-motion sickness agents. A second approach selects drugs that are used to prevent emesis caused by means other than exposure to motion. The third approach relies on basic research that characterizes individual differences in susceptibility. The hypothesis is: detection of individual differences leads to identification of specific drugs, which target physiologic systems that show individual differences. These physiologic systems are targets for therapy and may play a role in the etiology of SMS. Two drugs that reduce susceptibility to SMS include dexamethasone and d(CH2)5Tyr(Me)AVP, a vasopressin (AVP)V1 antagonist. The latter peptide has demonstrated complete blockade of emesis and other significant symptoms in squirrel monkeys. These studies were predicated on observations that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistances. Investigations are underway to test a 0.5-mg intravenous dose in humans. Kappa opioid agonists inhibit AVP release and offer new therapeutic possibilities and advantages over AVP peptides. This review details the experimental data collected on AVP and adrenocorticotropin. The literature supports interrelated roles for AVP and opioid peptides in SMS. Experimental testing of kappa agonists is warranted because specific opioid agonists act at neuroanatomical sites causing nausea and vomiting. It is argued opioid receptors in the chemoreceptor trigger zone and vomiting center stimulate and inhibit the emetic response, respectively. The evidence suggests kappa and/or mu receptors at VC are involved in inhibition of emesis, whereas delta opioid receptors at CTZ are involved in stimulation of emesis.

Facilitation of adaptation and acute tolerance to stressful sensory input by doxepin and scopolamine plus amphetamine.

This work characterizes a new methodologic and pharmacologic approach to control terrestrial and space motion sickness (SMS). The experimental design allowed separate evaluation of drug action on susceptibility and adaptability, and used repeated measures to approximate the chronic stressful motion of microgravity. Daily exposure to cross-coupled angular acceleration for 5 consecutive days demonstrated that the efficacy of doxepin and scopolamine plus amphetamine in the prevention of autonomic system dysfunction was not only apparent on the first test day (P < .01), but was also evident in the substantially enhanced resistance developed over the 5-day test period (P < .01) as compared with placebo. This indicates that daily use of these medications does not diminish therapeutic efficacy (tolerance). The efficacy of doxepin was anticipated because it possesses pharmacologic properties similar to those of established anti-motion sickness drugs. Comparable efficacy after doxepin loading for 4 hours, 3 days, or 21 days suggests a mechanism distinct from its antidepressant effects, possibly related to its potent antihistaminergic actions. Use of doxepin has operational significance to the National Aeronautics and Space Administration, in comparison with current preparations of scopolamine plus amphetamine, because of doxepin's minimal impact on cognitive performance, and most importantly, its favorable pharmacokinetic profile, particularly its long half-life.

Investigation of anti-motion sickness drugs in the squirrel monkey.

Early attempts to develop an animal model for anti-motion sickness drugs, using dogs and cats; were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti-motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800-1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti-motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3-6.0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.

Etiologic significance of arginine vasopressin in motion sickness.

There is abundant evidence implicating the role of arginine vasopressin in motion sickness. The effects of AVP analogs on motion sickness were investigated in squirrel monkeys. Two specific V1 antagonists (SK&F 100273 and SK&F 103561) and three mixed V1/V2 antagonists (SK&F 101926, SK&F 105494, and SK&F 104146-D) were tested on six highly susceptible monkeys. Intravenous injections of 200 ug of a V1 antagonist abolished emesis in all six monkeys, and few prodromal symptoms remained (latency to emesis > 120 minutes, P < .001). Mixed V1/V2 antagonists failed to abolish emesis in all monkeys. However, there was a slight increase in the latency to the first bout of emesis/retching with the mixed antagonists when compared with the baseline. The dose-response relationship and rate of onset of action of the V1 antagonists (SK&F 100273) were explored. Latency to the first bout of emesis/retching increased to about twice that of the baseline when half of the effective antiemetic dose was used. The efficacy demonstrated by the specific V1 antagonists indicates that V1 receptors may modulate emesis.

Induction of tolerance and withdrawal in rats receiving morphine in the spinal subarachnoid space.

Rats implanted with chronic catheters in the spinal subarachnoid space were given twice daily injections for 7 days of morphine sulfate, either intrathecally into the lumbar subarachnoid space (15 or 50 microng) or i.p. (20 mg/kg). The development of tolerance, as manifested in a reduction of the analgetic efficacy of these injections on the hot plate and tail flick, occurred in a dose dependent fashion over a period of 7 days. At this time, injections of i.p. morphine into animals which had received spinal morphine and vice versa revealed the existence of a two way cross tolerance between spinal and systemically administered morphine. Injection of naloxone into the spinal cord of animals exposed to i.p. morphine or conversely, i.p. naloxone in animals tolerant to intrathecal morphine, yielded a hyperreflexia and extreme sensitivity to handling. Other signs commonly observed in percipitated withdrawal, however, such as wet shakes and weight loss, were not observed.

Biphasic effects of the antiserotonergic methysergide on lordosis in rats.

As also reported by other workers, the antiserotonergic drug methysergide was found to facilitate lordotic responding in estrogen primed, ovariectomized rats. A second dose of methysergide 24 hr after the first, however, failed to produce any increment in responding. Animals received daily estrogen injections in order to maintain a relatively constant level of priming. After several days of methysergide, a progesterone injection facilitated lordosis to the same degree as in controls receiving only saline and estrogen. When a second injection of progesterone was given 24 hr later, however, the animals failed to respond. In contrast, saline controls with this estrogen paradigm responded equally well to both progesterone injections. These results are discussed in terms of their bearing on possible serotonergic and non-serotonergic mechanisms by which progesterone may control lordosis.

Sodium concentration in saliva along the time course of experimental Coriolis sickness.

Procedures designed to evaluate the severity of motion sickness have included subjective reporting of changes in salivation. In order to increase objectivity, we studied the sodium concentration of saliva, which is directly related to the flow rate. Healthy adults with normal vestibular function underwent a modified Coriolis Sickness Susceptibility Index (CSSI) test, utilizing a staircase profile. Saliva was collected without interrupting the stimulus by means of cotton placed beneath the subject's tongue for one minute. Samples were obtained 5 min prior to stimulation, 30 and 45 min following stimulus onset, and/or upon reaching the "nausea II" endpoint. Saliva for analysis by atomic absorption spectrophotometry was obtained by centrifugation of the cotton. A significant difference in sodium concentration was found between the baseline and 30-min sample (p less than 0.01). Although the amount of salivation was rather variable, the pattern of changes in sodium concentration was similar in all experimental cases.

Mechanisms of selective attention and space motion sickness.

The neural mismatch theory of space motion sickness asserts that the central and peripheral autonomic sequelae of discordant sensory input arise from central integrative processes falling to reconcile patterns of incoming sensory information with existing memory. Stated differently, perceived novelty reaches a stress level as integrative mechanisms fail to return a sense of control to the individual in the new environment. Based on evidence summarized here, the severity of the neural mismatch may be dependent upon the relative amount of attention selectively afforded to each sensory input competing for control of behavior. Components of the limbic system may play important roles in match-mismatch operations, be therapeutically modulated by antimotion sickness drugs, and be optimally positioned to control autonomic output.

Failure of metoclopramide to control emesis or nausea due to stressful angular or linear acceleration.

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, we were unable to demonstrate any significant (p less than 0.05) effects of this drug on motion sickness.

Autonomic function and plasma catecholamines following stressful sensory stimuli.

This experimentation defined a limited role for epinephrine in the autonomic nervous system function and the nausea that occurred following motion sickness testing. Individual responses to stressful sensory stimuli and nausea, as reflected by rising peripheral levels of epinephrine, were not significantly diminished upon repeated exposure and adaptation to the stressor. However, subjects who demonstrated more robust elevations of epinephrine in response to nausea displayed higher resistances to stressful motion stimuli. Modulation of peripheral catecholaminergic function with dexamethasone, or scopolamine plus amphetamine, suggested that altered autonomic nervous system function and nausea following motion sickness testing were not mediated by peripheral catecholamine receptor stimulation. Marked differences were noted in individual responses to drug and systemic responses of epinephrine and norepinephrine. It is possible that responses in epinephrine to motion sickness testing may predict resistance to stressful motion, and represent a peripheral manifestation of some as yet unknown central event of etiologic relevance.

beta-Endorphin and arginine vasopressin following stressful sensory stimuli in man.

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 adrenocorticotropin (ACTH) to the extent that all hormones rise in response to motion sickness (p < 0.003). Repeated exposure diminished motion-induced release of ENDO (p < 0.005) and AVP (p < 0.004) despite a three-fold increase in resistance to motion stimuli. Higher post-stress levels of AVP (p < 0.04) and ACTH (p < 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 individuals 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.

Hormonal responses of metoclopramide-treated subjects experiencing nausea or emesis during parabolic flight.

Metoclopramide was orally administered (10 or 20 mg) to 22 subjects, 75 min before parabolic flight. Serum levels of ACTH, EPI, NE, and vasopressin (AVP) were unaltered by metoclopramide. AVP and ACTH (1.2 and 36 pg.ml-1) were elevated 77 and 3.8-fold (92.3 and 135 pg.ml-1) following emesis, after 40 parabolas (68.7 and 140 pg.ml-1) and landing (8.7 and 79 pg.ml-1). Seven subjects displaying no nausea and no emesis demonstrated smaller elevations (8.2 and 2.2-fold). Of 15 vomiting subjects, 7 reported no nausea and had lower elevations of AVP with faster recoveries. These findings are consistent with Rowe's suggestion (1979) that nausea may correlate with AVP release. Inhibition of AVP release by fluid shifts during microgravity might account for our findings and astronaut-reported episodes of vomiting without nausea. Elevations in EPI followed emesis or exposure to 40 parabolas whether emesis occurred or not. Only emesis elevated NE (578 to 840 pg.ml-1).

Endocrine correlates of susceptibility to motion sickness.

Motion sickness releases ACTH, epinephrine, and norepinephrine. We are interested in endocrine responses to motion sickness, in adaptive responses leading to the resolution of the syndrome, and in how antimotion-sickness drugs influence the endocrine responses. Susceptible or insusceptible subjects were administered antimotion-sickness drugs prior to stressful stimulation. Insusceptible subjects displayed more pronounced elevations of ACTH, epinephrine, and norepinephrine after stressful motion. Predrug levels of ACTH were higher in insusceptible subjects (p less than 0.01). Acute blockade of hormone responses to stressful motion or alteration of levels of ACTH by drugs was not correlated with individual susceptibility. No correlation was apparent between epinephrine and ACTH release. These endocrine differences may represent neurochemical markers for susceptibility to motion, stress, or general adaptability, and it may be that the chronic modulation of their levels might be more effective in preventing motion sickness than the acute blockade or stimulation of specific receptors.

Sensory conflict theory of space motion sickness: an anatomical location for the neuroconflict.

Most investigators understand sensory conflict to mean a discontinuity between either visual, proprioceptive, and somatosensory input, or semicircular canal and otolith input. Few hypotheses have attempted to define specific physiological mechanisms linking the conflict with the sickness. Suggestions that the theory be renamed the neural mismatch theory allow for the possibility that central integrative mechanisms are involved in interpreting the significance of the sensory environment and that the conflict between visual or vestibular input systems or between separate components of the vestibular system is of secondary importance to mismatch occurring between ongoing sensory experience and long-term memory. This paper describes the role of the limbic system in integration of sensory information and long-term memory, in the expression of the symptoms of motion sickness, and the impact of anti-motion sickness drugs and stress hormones on limbic system function. The limbic system may be the neural mismatch center of the brain.

Mechanisms underlying the antimotion sickness effects of psychostimulants.

The major conclusions of this review are: 1) that selective enhancement of dopaminergic transmission, not noradrenergic, is sufficient to account for amphetamine-induced resistance and perhaps 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 the brainstem vestibular areas, can account for the therapeutic synergism of scopolamine and amphetamine. The therapeutic actions of psychostimulants may be dissociable from some of their side effects, particularly cardiovascular effects related to peripheral norepinephrine release. Drugs which target specific subtypes of dopaminergic receptors may serve this purpose.

Efficacy of phosphatidylcholine in the modulation of motion sickness susceptibility.

This study evaluated the efficacy of pharmacological doses of phosphatidylcholine (lecithin) in the modulation of motion sickness induced by exposure to coriolis stimulation in a rotating chair. Subjects received daily dietary supplements of 25 grams of lecithin (90% phosphatidylcholine) and were tested for their susceptibility to motion sickness after 4 h, 2 d, and 21 d. A small but statistically significant increase in susceptibility (+ 15%) was noted 4 h after supplemental phosphatidylcholine, with four of nine subjects demonstrating a marked increase in susceptibility. We attributed this finding to choline's stimulatory action on cholinergic systems, an action which opposes that of the classical antimotion sickness drug scopolamine. Chronic lecithin loading revealed a trend towards reduced susceptibility, possibly indicating the occurrence of adaptive mechanisms such as receptor down-regulation. Withdrawal from lecithin loading, perhaps coupled with anticholinergic treatment, might prove to be a potent prophylactic regimen and ought to be tested.

Control of nausea and autonomic dysfunction with terfenadine, a peripherally acting antihistamine.

Terfenadine (Seldane) was administered to 14 male subjects in a randomized, double-blinded, and crossed-over design to assess the efficacy of this peripherally active antihistamine as an anti-motion 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 us to conclude that because the drug does not or only poorly crosses the blood-brain barrier, a selective peripheral antihistamine (H1) 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 anti-motion 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.

Arousal and stability: the effects of five new sympathomimetic drugs suggest a new principle for the prevention of space motion sickness.

Sympathomimetic agents are frequent components in antimotion-sickness drug combinations because of their usefulness in counteracting the sedation caused by stressful motion or resulting from the administration of other antimotion-sickness drugs. The noradrenergic neurochemistry of the brain's arousal-attentional systems prompted us to evaluate the efficacy of five new sympathomimetic drugs and to further define the role of arousal in susceptibility to motion. Subjects were orally administered methamphetamine (20 mg), phenmetrazine (25 mg), phentermine (37.5 mg), methylphenidate (20 mg), or pemoline (75 mg) 2 h prior to taking a Staircase Profile Test. All of the drugs increased resistance to stressful coriolis stimulation by 80-120%. Methylphenidate and pemoline showed fewer side effects. These findings, interpreted in conjunction with the documented inefficacy of most anticholinergic and antihistaminergic drugs tested to date, suggest that sympathomimetic drugs or a generalized state of arousal can inhibit the development of motion sickness.

Lack of effects of astemizole on vestibular ocular reflex, motion sickness, and cognitive performance in man.

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 1 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 us to conclude 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.