title: First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain.
abstract: Growing evidence supports the idea that in addition to their well established role in the immune system, chemokines might play a role in both normal and pathological brain function, and the chemokine network could interact with other neuromodulators. The chemokine stromal cell-derived growth factor (SDF)-1alpha/CXCL12, a member of the CXC chemokine family, was tested for its possible effect on the analgesic responses of the cannabinoid receptor agonist aminoalkylindole 4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo-[3,2,1ij]quinolin-6-one [(+)-WIN 55,212-2, hereafter WIN 55,212-2] at the level of the periaqueductal gray (PAG), a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds. The administration of WIN 55,212-2 (0.1-0.4 microg/microl) into the PAG resulted in antinociception in a dose-dependent manner. The selective cannabinoid (CB)1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A; 1-10 microg) given into the PAG blocked the WIN 55,212-2-induced antinociception. In contrast, the selective CB2 antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 10 microg) did not alter the WIN 55,212-2-induced antinociception. Pretreatment with SDF-1alpha/CXCL12 (100 ng) caused a reduction in antinociceptive responses of WIN 55,212-2. The inhibitory effect of SDF-1alpha/CXCL12 on WIN 55,212-2-induced antinociception was reversed by octahydrochloride [corrected] hydrate (AMD 3100) (10-50 ng), an antagonist of the SDF-1alpha/CXCL12, acting at its receptor, CXCR4. This study reports the first in vivo evidence of a functional interaction between chemokine and cannabinoid systems in the brain, showing that the activation of SDF-1alpha/CXCL12 receptors (CXCR4) in the PAG interferes with the analgesic effects of WIN 55212-2.
authors.affiliation: Center of Substance Abuse Research, Temple University School of Medicine, 3400 N. Broad St., Philadelphia, PA 19140, USA. kbenamar@temple.edu
authors.forename: Khalid
authors.initials: K
authors.lastname: Benamar
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Geller
authors.forename: Martin W
authors.initials: MW
authors.lastname: Adler
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D048588:Benzoxazines / Q000627:therapeutic use*; D001892:Camphanes / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000627:therapeutic use*; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D009281:Naphthalenes / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D000077285:Rimonabant
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D001892:Camphanes; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D019718:Receptors, CXCR4; C110630:SR 144528; 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