Imiquimod-elicited emesis is mediated by the area postrema, but not by direct neuronal activation.
The immunomodulator, imiquimod, has been shown to have antiviral and antitumor properties in animal models. It also has been reported to alter cytokine levels in both animals and humans. However, because imiquimod appeared to be emetic, studies were conducted to determine the degree of sensitivity, and the pathways involved. Subcutaneous administration of > or = 10 mg/kg imiquimod to ferrets elicited emesis with latencies as short as 2'; 12 and 15 mg/kg were optimal doses. Emetic responsiveness was eliminated by complete ablation of the area postrema, but was unaffected by bilateral supradiaphragmatic section of the vagus nerve. This indicates that the emesis is produced by an activation of the chemoreceptor trigger zone B the area postrema. Ferret brain stem slices (450 microm) were preincubated in oxygenated Krebs-Ringer and then mounted in a submerged slice recording chamber. Extracellular recordings of spontaneous and ionophoretically evoked activity of area postrema neurons were obtained for up to 8 h, while the effect of bath-applied imiquimod was determined. Under control conditions, neurons showed a low frequency spontaneous discharge. Introduction of imiquimod (concentration range, 1 x 10(-7) to 5 x 10(-8)M) had no effect on neuronal firing. With ionophoresis of glutamate from an independent micropipette, a brief excitatory response was obtained. We conclude that imiquimod does not directly excite area postrema neurons. It is likely that imiquimod causes synthesis and release of some unknown emetic substance(s), very possibly cytokines.
Strominger
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Albany Medical College, Albany, NY 12208, USA. stromin@mail.amc.edu
Brady
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R
Gullikson
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Carpenter
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DO
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001933:Brain Stem / Q000502:physiology*; D004594:Electrophysiology; D005289:Ferrets; D000077271:Imiquimod; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000502:physiology; D014628:Vagotomy; D014839:Vomiting / Q000139:chemically induced*
D000634:Aminoquinolines; D000077271:Imiquimod