Vertigo and motion sickness. Part II: pharmacologic treatment

Ear, Nose & Throat Journal, Jan, 2006 by Timothy P. Zajonc, Peter S. Roland

New horizons

Serotonergic agonists and antagonists. Serotonin (5-hydroxytryptophan [5-HT]) is an indole amine found throughout the body. Its effects are mediated via 5-HT receptors. The 5-H[T.sub.1], 5-H[T.sub.2], 5-H[T.sub.3], 5-H[T.sub.4], and 5-H[T.sub.5] receptors have been identified in vivo. Additional 5-H[T.sub.1] and 5-H[T.sub.2] receptor subclasses have been identified and characterized, as well. (59)

The 5-H[T.sub.1A] receptors are probably present in the vestibular nuclei and elsewhere in the emetic pathway. (60) In cats, 5-H[T.sub.1A] receptor agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been shown to prevent vomiting elicited by both motion-induced and chemical-induced nausea. (61-63)

Biver et al studied the distribution of 5-H[T.sub.2], receptors in human brain tissue via positron-emission tomography. (64) A radiotracer specific for 5-H[T.sub.2] receptors revealed a primarily cortical distribution; these receptors were found to a lesser extent in the basal ganglia and cerebellum. A 5-H[T.sub.2] agonist--1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)--has been shown to block emesis induced by motion and cisplatin in an animal model. (65,66)

The 5-H[T.sub.3] receptors are present in high densities in both the central and peripheral nervous systems. They are found in the area postrema, nucleus of the tractus solitarius, cerebral cortex, spinal cord, and visceral autonomic and sensory nerves. (67) The 5-H[T.sub.3] receptor antagonists (e.g., ondansetron) are used extensively for the control of postoperative nausea and vomiting. Stott et al demonstrated that their antinausea effect does not prevent motion-induced vomiting. (68)

Selective serotonin reuptake inhibitors (SSRIs) work by increasing synaptic concentrations of serotonin. Imipramine (a tricyclic antidepressant with strong serotonergic properties) and fluoxetine (an SSRI) have been tested in the animal model Suncus murinus. (66) Both agents exhibited dose-dependent effectiveness in preventing motion sickness. Their usefulness in humans is not yet clear.

Neurokinin receptors. Neurokinin type 1 (N[K.sub.1]) receptors are naturally bound by substance R and they are involved in a variety of processes, including smooth muscle relaxation or contraction, neuronal depolarization, and exocrine gland secretion. Substance P is a peptide neurotransmitter that is localized to many neuronal structures. Substance P is believed to play a role in the transmission of sensory information, particularly that associated with noxious stimuli, from the periphery to central structures. Some N[K.sub.1] receptor antagonists have been shown to have strong antiemetic properties. One of the most selective N[K.sub.1] receptor antagonists, GR203040, has demonstrated effectiveness against motion-induced emesis in animal models. (69) It should be noted that although this drug is highly selective for N[K.sub.1] receptors, it has some affinity for [H.sub.1] receptors. (70) In human studies, however, N[K.sub.1] receptor antagonists alone and in combination with the 5-H[T.sub.3] receptor antagonist ondansetron have proven to be no more effective than placebo in the treatment of motion-induced nausea in humans. (71) The fact that N[K.sub.1] receptor antagonists have demonstrated effectiveness in preventing chemotherapy-induced nausea but not motion sickness-induced nausea suggests that there is a different mechanism of action for motion-induced nausea.