Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Analgesics / pharmacology
-
Animals
-
Benzoxazines / pharmacology
-
Brain Stem / anatomy & histology
-
Brain Stem / drug effects*
-
Brain Stem / metabolism
-
Cannabinoid Receptor Modulators / metabolism*
-
Cimetidine / analogs & derivatives*
-
Cimetidine / pharmacology
-
Male
-
Microinjections
-
Morpholines / pharmacology
-
Naphthalenes / pharmacology
-
Neural Pathways / anatomy & histology
-
Neural Pathways / drug effects
-
Neural Pathways / metabolism
-
Nociceptors / drug effects*
-
Nociceptors / metabolism
-
Pain / drug therapy*
-
Pain / metabolism
-
Pain / physiopathology
-
Pain Measurement / drug effects
-
Pain Threshold / drug effects
-
Pain Threshold / physiology
-
Periaqueductal Gray / anatomy & histology
-
Periaqueductal Gray / drug effects
-
Periaqueductal Gray / metabolism
-
Piperidines / pharmacology
-
Pyrazoles / pharmacology
-
Raphe Nuclei / anatomy & histology
-
Raphe Nuclei / drug effects
-
Raphe Nuclei / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Receptor, Cannabinoid, CB1 / agonists
-
Receptor, Cannabinoid, CB1 / metabolism
-
Rhombencephalon / anatomy & histology
-
Rhombencephalon / drug effects
-
Rhombencephalon / metabolism
-
Rimonabant
Substances
-
Analgesics
-
Benzoxazines
-
Cannabinoid Receptor Modulators
-
Morpholines
-
Naphthalenes
-
Piperidines
-
Pyrazoles
-
Receptor, Cannabinoid, CB1
-
SKF 92374
-
(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
-
Cimetidine
-
Rimonabant