First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain

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)-1 alpha/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 mu g/mu l) 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 mu g) 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 mu g) did not alter the WIN 55,212-2-induced antinociception. Pretreatment with SDF-1 alpha/CXCL12 (100 ng) caused a reduction in antinociceptive responses of WIN 55,212-2. The inhibitory effect of SDF-1 alpha/CXCL12 on WIN 55,212-2-induced antinociception was reversed by octahydrochloride hydrate (AMD 3100) (10-50 ng), an antagonist of the SDF-1 alpha/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-1 alpha/CXCL12 receptors (CXCR4) in the PAG interferes with the analgesic effects of WIN 55212-2.