Non-opioid antinociception produced by brain stem injections of improgan: significance of local, but not cross-regional, cannabinoid mechanisms.
Improgan, a cimetidine derivative which lacks activity at known histamine, opioid or cannabinoid receptors, acts by an unknown mechanism in the periaqueductal gray (PAG) and raphe magnus (RM) to stimulate descending, analgesic circuits. These circuits may utilize cannabinoid mechanisms. To characterize further the nature of these circuits, the effects of intracerebral (i.c.) microinjections of rimonabant (a CB(1) receptor inverse agonist) were studied on antinociceptive responses following i.c. microinjections of improgan and the cannabinoid agonist WIN 55,212 (WIN) in rats. Separate intra-RM injections of improgan (30 microg) and WIN (8 microg) produced near-maximal antinociception on both the hot plate (HP) and tail flick (TF) nociceptive tests. Pretreatment with intra-RM rimonabant (20 microg) antagonized the antinociception produced by both intra-RM improgan and intra-RM WIN, but had no effects when given alone. Similar studies with improgan demonstrated rimonabant-sensitive sites within the dorsal and ventrolateral PAG. However, intra-RM pretreatment with rimonabant had no effect on antinociceptive responses following intra-PAG improgan. These studies show that improgan activates pain-relieving mechanisms in the PAG and the RM, both of which may utilize local cannabinoid mechanisms.
Hough
Lindsay B
LB
Center for Neuropharmacology and Neuroscience, Albany Medical College MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. houghl@mail.amc.edu
Svokos
Konstantina
K
Nalwalk
Julia W
JW
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001933:Brain Stem / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009434:Neural Pathways / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010487:Periaqueductal Gray / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011903:Raphe Nuclei / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D012249:Rhombencephalon / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D000077285:Rimonabant
D000700:Analgesics; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C099531:SKF 92374; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002927:Cimetidine; D000077285:Rimonabant