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Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats.

AbstractBACKGROUND AND PURPOSE:
Cannabinoid CB(1) receptor antagonists/inverse agonists, potentiate toxin-induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB(1) receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist.
EXPERIMENTAL APPROACH:
The conditioned gaping model of nausea in rats was used to compare the CB(1) receptor antagonist/inverse agonist, AM251, and the CB(1) receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl-induced gaping in this model was also evaluated.
KEY RESULTS:
At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg.kg(-1)) potentiated LiCl-induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg.kg(-1) of AM6545 and AM6527 neither potentiated LiCl-induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 microg) or the 4th ventricle (2.5, 12.5 and 125 microg) did not potentiate LiCl-induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test.
CONCLUSIONS AND IMPLICATIONS:
Inverse agonism, but not neutral antagonism, of CB(1) receptors potentiated toxin-induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB(1) receptors, located distal to the cerebral ventricles.
AuthorsC L Limebeer, V K Vemuri, H Bedard, S T Lang, K P Ossenkopp, A Makriyannis, L A Parker
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 161 Issue 2 Pg. 336-49 (Sep 2010) ISSN: 1476-5381 [Electronic] England
PMID20735419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • AM 6527
  • AM6545
  • Morpholines
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251
  • Saccharin
  • Lithium Chloride
Topics
  • Administration, Oral
  • Animals
  • Brain (drug effects, metabolism)
  • Conditioning, Classical
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Feeding Behavior (drug effects)
  • Lithium Chloride
  • Male
  • Morpholines (administration & dosage, pharmacology)
  • Nausea (chemically induced, metabolism)
  • Piperidines (administration & dosage, pharmacology)
  • Pyrazoles (administration & dosage, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 (agonists, antagonists & inhibitors)
  • Saccharin (administration & dosage)

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