title: 'Knock-down' of spinal CB1 receptors produces abnormal pain and elevates spinal dynorphin content in mice.
abstract: Recent studies demonstrate the possible existence of tonic modulatory control of nociceptive input mediated by spinal cannabinoid receptors (CB1). Accordingly, it is predicted that a reduction in the spinal CB1 receptors may enhance sensitivity to sensory stimuli and a decrease in spinal antinociceptive potency to cannabinoid agonists. An antisense oligodeoxynucleotide (ODN) specific to the CB1 receptor was used to 'knock-down' CB1 receptors in the lumbar spinal cord and dorsal root ganglia by the local, repeated intrathecal (i.th.) administration of the ODN. This treatment resulted in a decrease in lumbar spinal CB1 receptor expression accompanied by a decrease in the response thresholds to both innocuous tactile and noxious thermal stimuli. The antinociceptive action of the CB1 agonist, WIN 55,212-2, by i.th. administration was also significantly attenuated after treatment with the antisense ODN. Similar treatment using a mismatch control ODN had no effect on receptor protein or on sensory thresholds. The effects of the antisense ODN treatment on sensory thresholds were fully reversed after discontinuation of the ODN injection. The antisense ODN treated rats also showed a significant increase in lumbar spinal dynorphin A. Acute i.th. injection of MK-801 or an antidynorphin antiserum blocked the antisense ODN-induced tactile and thermal hypersensitivity. These data support the possibility of endogenous inhibitory cannabinoid tone to limit spinal afferent input of thermal and tactile stimuli. Lifting of this inhibitory tone through a 'knock-down' of spinal CB1 receptors apparently lowers the thresholds for sensory input, as reflected by the actions of MK-801 to block tactile and thermal hypersensitivity. The increased spinal dynorphin may act to further promote afferent outflow and abnormal pain because sequestration of spinal dynorphin with antiserum also reverses the manifestations of abnormal pain following knock-down of CB1 receptors.
authors.affiliation: Department of Pharmacology, School of Medicine, Gülhane Military Medical Academy, 06018, Etlik, Ankara, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogrul
authors.forename: Luis R
authors.initials: LR
authors.lastname: Gardell
authors.forename: Shouwu
authors.initials: S
authors.lastname: Ma
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D048588:Benzoxazines; D003511:Cyclohexanols / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004399:Dynorphins / Q000276:immunology / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000378:metabolism*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D014316:Tritium
chemical_list: D000700:Analgesics; D000906:Antibodies; D048588:Benzoxazines; D003511:Cyclohexanols; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D009281:Naphthalenes; D020319:Oligodeoxyribonucleotides, Antisense; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014316:Tritium; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D016291:Dizocilpine Maleate; D004399:Dynorphins; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol