Physiological evidence for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain

Background and purpose: The chemokine, stromal cell-derived growth factor-1 alpha (SDF-1 alpha/CXCL12), a member of the CXC chemokine family, and the ligand for CXCR4, the co-receptor involved in the entry of human immunodeficiency virus-1 (HIV-1), was tested for its possible interaction with a physiological response to a cannabinoid. Experimental approach: The cannabinoid agonist, an aminoalkylindole, (+)-WIN 55,212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], was infused directly into the preoptic anterior hypothalamus (POAH), the primary brain area involved in thermoregulation. Key results: WIN 55,212-2 (5-15 mu g) evoked a dose-related hypothermia, which was attenuated by SDF-1 alpha/CXCL12 microinjected directly into the POAH. The inhibitory effect of SDF-1 alpha/CXCL12 on WIN 55,212-2-induced hypothermia was reversed by 1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] octohydrobromide dihydrate, an antagonist of SDF-1 alpha/CXCL12, acting at its receptor, CXCR4. Conclusion and implications: This study provides the first in vivo evidence for a thermoregulatory interaction between the HIV-1 co-receptor and the cannabinoid system in the brain.