Alteration of neuronal CXCR4 function by in vivo/in vitro opiates treatments and its role in neuronal survival and HIV neuropathogenesis

• Published in: Journal of neurovirology Vol. 13; p. 11
• Main Author: Meucci, O
• Format: Journal Article
• Language: English
• Published: 01.01.2007
• Subjects: Human immunodeficiency virus 1
• ISSN: 1355-0284

Studies suggest that opiates may exacerbate the neurological complications of HIV-1 through direct actions in the CNS. Our goal is to determine the effects of mopioid receptor (MOR) agonists on the signaling pathways activated by CXCR4-one of the major HIV coreceptors, which also plays critical roles in neuronal survival and differentiation. In particular, we use in vitro and in vivo approaches to establish the effects of MOR agonists on the coupling of CXCR4 to neuronal survival mechanisms. Our data show that longterm treatment of rat primary cortical cultures with DAMGO, morphine or endomorphin-1 inhibits activation of ERK1/2 and Akt by CXCL12-an effect that is not mediated by changes in CXCR4 levels on neuronal surface. Pretreatment with MOR agonists also prevents the neuroprotective action of CXCL12 in NMDA-treated cultures. MOR and CXCR4 are co-expressed in many cultured neurons suggesting a possible crosstalk between the two receptors. This is supported by GTPgS incorporation studies in rat brain slices and brain homogenates measuring levels of G-protein activation upon stimulation of CXCR4 or MOR. These studies also show that in vivo morphine treatments inhibit CXCR4-mediated G-protein activation. Experiments with glia-free cultures demonstrate that the inhibitory effect of opioids on CXCR4 signaling is independent of glia, and that opioid treatment blocks CXCL12-mediated phosphorylation on specific residues of the C-terminus of CXCR4, which is involved in receptor activation/desensitization. Down-regulation of phospho-CXCR4 was also found in brain tissue from HIV/HAD patients, suggesting that impairment of CXCR4 function by opioids may contribute to HIV neuropathology.