Critical role of the endogenous cannabinoid system in mouse pup suckling and growth.
Delta9-tetrahydrocannabinol, the active principle in marijuana, is a cannabinoid receptor agonist. Both the crude drug and delta9-tetrahydrocannabinol have been used as appetite promoters. The endogenous cannabinoid, arachidonoyl ethanolamide (anandamide), likewise a cannabinoid receptor agonist, has been shown to have the same effect. In contrast, the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (SR141716A) reduces food intake. Here, we report that administration of SR141716A to newly born mouse pups (either a single administration on postnatal day 1, or daily for a week as of postnatal day 2) had a devastating effect on milk ingestion and growth. The first 24 h after birth appeared the most critical for the growth stunting effect of SR141716A. Death followed within 4-8 days. Co-administration of delta9-tetrahydrocannabinol almost fully reversed the effect of the antagonist in the week-long regimen. Co-administration of 2-arachidonoyl glycerol, an endocannabinoid, with 2-palmitoyl glycerol and 2-linoleoyl glycerol, which enhance 2-arachidonoyl glycerol potency, resulted in a significant delay in mortality rates caused by the antagonist. We conclude that the endocannabinoid system plays a vital role in milk suckling, and hence in growth and development during the early stages of mouse life.
Fride
E
E
Department of Medicinal Chemistry and Natural Products, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Ginzburg
Y
Y
Breuer
A
A
Bisogno
T
T
Di Marzo
V
V
Mechoulam
R
R
D000818:Animals; D000831:Animals, Newborn; D001066:Appetite / Q000187:drug effects*; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators; D002851:Chromatography, High Pressure Liquid; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids; D006128:Growth / Q000187:drug effects; D051379:Mice; D008892:Milk / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; D000077285:Rimonabant; C078814:anandamide