title: Morphine induces the release of CCL5 from astrocytes: potential neuroprotective mechanism against the HIV protein gp120.
abstract: A number of human immunodeficiency virus type-1 (HIV) positive subjects are also opiate abusers. These individuals are at high risk to develop neurological complications. However, little is still known about the molecular mechanism(s) linking opiates and HIV neurotoxicity. To learn more, we exposed rat neuronal/glial cultures prepared from different brain areas to opiate agonists and HIV envelope glycoproteins gp120IIIB or BaL. These strains bind to CXCR4 and CCR5 chemokine receptors, respectively, and promote neuronal death. Morphine did not synergize the toxic effect of gp120IIIB but inhibited the cytotoxic property of gp120BaL. This effect was blocked by naloxone and reproduced by the mu opioid receptor agonist DAMGO. To examine the potential mechanism(s) of neuroprotection, we determined the effect of morphine on the release of chemokines CCL5 and CXCL12 in neurons, astrocytes, and microglia cultures. CCL5 has been shown to prevent gp120BaL neurotoxicity while CXCL12 decreases neuronal survival. Morphine elicited a time-dependent release of CCL5 but failed to affect the release of CXCL12. This effect was observed only in primary cultures of astrocytes. To examine the role of endogenous CCL5 in the neuroprotective activity of morphine, mixed cerebellar neurons/glial cells were immunoneutralized against CCL5 prior to morphine and gp120 treatment. In these cells the neuroprotective effect of opiate agonists was blocked. Our data suggest that morphine may exhibit a neuroprotective activity against M-tropic gp120 through the release of CCL5 from astrocytes.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Avdoshina
authors.forename: Francesca
authors.initials: F
authors.lastname: Biggio
authors.forename: Guillermo
authors.initials: G
authors.lastname: Palchik
authors.forename: Lee A
authors.initials: LA
authors.lastname: Campbell
authors.forename: Italo
authors.initials: I
authors.lastname: Mocchetti
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018946:Chemokine CCL5 / Q000378:metabolism*; D003561:Cytarabine / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000009:adverse effects*; D006624:Hippocampus / Q000166:cytology; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D018946:Chemokine CCL5; D015699:HIV Envelope Protein gp120; D009294:Narcotics; D003561:Cytarabine; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine