Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV‐1 tat transgenic mice

Abstract

HIV encephalitis (HIVE) is accompanied by brain inflammation, leukocyte infiltration, and glial activation, and HIV patients who abuse opiates are more likely to develop HIVE. To better understand how opiates could alter HIV-related brain inflammation, the expression of astrocyte (GFAP immunoreactivity) and macrophage/microglial (F4/80 or Mac1 immunoreactivity) markers in the striatum, and the percentage of 3-nitrotyrosine (3-NT) positive macrophages/microglia, was determined following a 2 day exposure to morphine (5 mg/kg/day via time-release, subcutaneous implant) and doxycycline in GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic mice. Data show that both morphine and Tat induction via doxycycline increased astrocyte activation, with significant additive increases achieved with combined morphine and doxycycline exposure. By contrast, combined Tat induction and morphine exposure, but neither manipulation alone, significantly increased the proportion of macrophages/microglia present in the striatum of transgenic mice, although morphine exposure was necessary to elevate 3-NT co-detection in Mac1-positive macrophages/microglia. Finally, Tat induction increased the percentage of neurons expressing active caspase-3, and this was even more significantly elevated by co-administration of morphine. In spite of elevations in caspase-3, neuronal TUNEL reactivity was unchanged in all groups, even after 10 days of Tat induction. Importantly, co-administration of naltrexone completely antagonized the effects of morphine. These findings indicate that morphine rapidly and significantly increases the activation of astrocytes and macrophages/microglia in the brains of inducible Tat transgenic mice, supporting the theory that early inflammatory changes in glia could underlie the development of HIVE in opiate-abusing AIDS patients.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…3 for summary). Morphineinduced GFAP elevations were naltrexone-sensitive (Beitner-Johnson et al, 1993;Bruce-Keller et al, 2008), and could be blocked even by an ultra-low dose of naltrexone (Mattioli et al, 2010). Several general proinflammatory attenuators have been shown to block opioid-induced GFAP up-regulation, such as antioxidant cis-7-methyl-9-methoxy-5,5a,6,10b-tetrahydroindeno[2, 1-b]indole (H-290/51) (Sharma et al, 2010), ibudilast (Hutchinson et al, 2009a), fluorocitrate (Song and Zhao, 2001), propentofylline (Raghavendra et al, 2004a;Narita et al, 2006a,b;Holdridge et al, 2007), pentoxifylline, and minocycline (Mika et al, 2009).…”

Fulminant encephalopathy with basal ganglia hyperintensities in HIV-infected drug users

“…20 In transgenic mice that express the HIV-Tat protein, morphine exposure had profound effects in the basal ganglia. 21 Similarly, autopsy studies confirm injury to dopaminergic neurons in cocaine users. 22 Cocaine use is occasionally associated with persistent choreoathetosis, tics, and seizures.…”

Quantification of Cerebral Vascular Architecture using Two-photon Microscopy in a Mouse Model of HIV-induced Neuroinflammation

“…Figure 3 shows representative results obtained using the method presented in this paper. In this experiment, a transgenic mouse model of HIV neuroinflammation was used 10 . Production of the HIV virotoxin Tat was induced in Tat+ mice by doxycycline-infused food for 12 weeks.…”

“…This combined approach provides for a holistic quantitation of cerebral vascular parameters, since the in vivo thin-skull cortical window allows for the preservation of the cerebral environment, while ex vivo imaging of capillary networks in brain slices enables the reconstruction of complete, three-dimensional capillary networks -which can then be quantified using commercially available software. vascular structure, as previously described 7,10 . 3.…”