Central effects of the cannabinoid receptor agonist WIN55212-2 on respiratory and cardiovascular regulation in anaesthetised rats.
1 The primary aim was to study the central respiratory effects of cannabinoids (CB). To this end, the cannabinoid receptor agonist WIN55212-2 was injected into the cisterna magna of urethane-anaesthetised rats and changes in respiratory parameters were observed. The secondary aim was to observe the centrally elicited cardiovascular actions of WIN55212-2. Involvement of opioid mechanisms in the central effects of WIN55212-2 was also studied. 2 Intracisternal (i.c.) application of WIN55212-2 (1, 3, 10 and 30 microg kg(-1)) dose-dependently decreased the respiratory rate and minute volume. Tidal volume was slightly increased, whereas peak inspiratory flow remained unchanged. In addition, WIN55212-2 increased mean arterial pressure and the plasma noradrenaline concentration and decreased heart rate. 3 I.c. injection of WIN55212-3 (1, 3, 10 and 30 microg kg(-1)), an enantiomer of WIN55212-2 lacking affinity for cannabinoid receptors, elicited no effects. All effects of WIN55212-2 were prevented by the CB1 receptor antagonist SR141716 (2 mg kg(-1) i.v.). I.c. administration of the opioid receptor agonist DAMGO (0.1, 0.3, 1 and 3 microg kg(-1)) markedly lowered the respiratory rate, tidal volume, minute volume and peak inspiratory flow. These effects were attenuated by the opioid receptor antagonist naloxone (0.2 mg kg(-1) i.v.). In contrast, naloxone did not affect the respiratory and cardiovascular effects of i.c. administered WIN55212-2. 4 Our results show that activation of CB1 cannabinoid receptors in the brain stem depresses respiration and enhances sympathetic tone and cardiac vagal tone. Opioid mechanisms are not involved in these central cannabinoid effects.
Pfitzer
Torsten
T
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, D-79104 Freiburg i. Br., Germany.
Niederhoffer
Nathalie
N
Szabo
Bela
B
D000701:Analgesics, Opioid / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D002946:Cisterna Magna; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007267:Injections; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000097:blood; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects*; D000077285:Rimonabant; D013990:Tidal Volume / Q000187:drug effects
D000701:Analgesics, Opioid; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; D009638:Norepinephrine