Pharmaceutical Countermeasures Have Opposite Effects on the Utricles and Semicircular Canals in Man

Abstract

Introduction: Sensory conflicts in the vestibular system lead to motion sickness of which space motion sickness (SMS) is a special case. SMS affects up to 70% of the astronauts during the first 3 days in space. The search for effective countermeasures has led to several nonpharmacological and pharmacological approaches. The current study focuses on the effects of lorazepam (1 mg), meclizine (25 mg), promethazine (25 mg), and scopolamine (0.4 mg) on the vestibular system, with special focus on the canal and otolith functions separately. Methods: The study had a placebo-controlled, single blind, repeated measures design. Sixteen healthy volunteers were subjected to a total of 7 test sessions, the first and last being without intake of medication. Semicircular canal function was evaluated by means of electronystagmography and otolith function with unilateral centrifugation. The horizontal semicircular canal function was characterized by the vestibulo-ocular reflex (VOR) gain measured during earth vertical axis rotation as well as the total caloric response. The function of the utricles was represented by the utricular sensitivity, reflecting the ocular counter roll relative to the virtual induced head tilt. Results: Promethazine significantly decreased the semicircular canal and utricular parameters. Both scopolamine and lorazepam caused only a decrease in the utricular sensitivity, whereas meclizine only decreased the semicircular canal-induced VOR gain. Discussion: The results show that the drugs affected different areas of the vestibular system and that the effects can thus be attributed to the specific pharmacological properties of each drug. Meclizine, as an antihistaminergic and weak anticholinergic drug, only affected the VOR gain, suggesting a central action on the medial vestibular nucleus. The same site of action is suggested for the anticholinergic scopolamine since acetylcholine receptors are present and utricular fibers terminate here. The global vestibular suppression caused by promethazine is probably a consequence of its anticholinergic, antihistaminergic, and antidopaminergic properties. Based on the fact that lorazepam increased the affinity of gamma-aminobutyric acid (GABA) for the GABA_A-receptor and its effects on the utriculi, the site of action seems to be the lateral vestibular nucleus. Conclusion: Meclizine, scopolamine, and lorazepam selectively suppress specific parts of the vestibular system. Selective suppression of different parts of the vestibular system may be more beneficial for alleviating (space) motion sickness than general suppressive agents. Additionally, this knowledge may help the clinician in his therapeutic management of patients with either semicircular canal or otolith dysfunction.

Adaptation and Compensation of Vestibular Responses Following Superior Canal Dehiscence Surgery

“…This could include the loss of a subcritical volume of perilymph – a volume small enough to cause sagging of the membranous labyrinth but not complete atelectasis – or mild labyrinthine inflammation. The labyrinth on the intact side might be affected by three possible mechanisms: 1) Reduced neural contribution to the VOR from the operated side through commissural pathways, 2) Central adaptation by down regulation (21) and 3) Suppressive effects of anesthetic and postoperative medications on the vestibular system (22). …”

Motion Sickness: Current Knowledge and Recent Advance

“…Small RCTs have verified the effectiveness of the first‐generation H 1 antihistamines against MS, but the second generations were ineffective (Table ). Physiological studies suggested that dimenhydrinate, cinnarizine, and meclizine exerted a central action on the medial VN in which high density of H 1 and H 2 receptor were present , while the promethazine had global suppression effect on vestibular system, but all these antihistamines had no effect on the central autonomic regions . Betahistine, an H 3 receptor antagonist and a weak H 1 receptor agonist, is effective in the preventing seasickness and increases tolerability to Coriolis accelerations via reducing histamine release in medial VN .…”

Peripheral Vestibular Dysfunction in Patients With Primary Ciliary Dyskinesia

“…A full explanation of the protocol and theory for utricular centrifugation (UCF) has been published elsewhere [12][13][14]. In brief, utricular function was measured by the subjective visual vertical (SVV) during unilateral centrifugation [15].…”

“…The resulting utriculo-ocular reflex (UOR) causes ocular counter-roll in an opposite direction to the translation direction. At 400º/s the stimulated utricle is exposed to a centrifugal acceleration of ω 2 r=0.40 g, where ω is the angular velocity and r the distance between the axis of rotation and the stimulated utricle, giving rise to a tilt sensation of 11.2° [14]. UCF was scored as median SVV angle and gain in each position and utricular percentage weakness.…”