The direct contributions of astrocytes to opioid and HIV interactions have been discussed previously (Dutta and Roy 2012; Hauser et al. 2012; Reddy et al. 2012; Hauser and Knapp 2014). Subsets of astroglia can express MOR, DOR and KOR (Stiene-Martin and Hauser 1991; Eriksson et al. 1992; Ruzicka et al. 1995; Gurwell et al. 1996; Hauser et al. 1996; Peterson et al. 1998; Stiene-Martin et al. 1998, 2001), as well as endogenous opioid peptides (Vilijn et al. 1988; Shinoda et al. 1989; Spruce et al. 1990; Hauser et al. 1990; Low et al. 1992). It appears that the ‘early’ events triggering the release of proinflammatory cytokines (i.e., TNF-α and IL-1β) from astroglia can be mediated by HIV Tat exposure alone (El-Hage et al. 2005, 2006a, b, 2008a). Opioids enhance HIV-1-induced inflammation later during the inflammatory cascade by exacerbating the sustained release of CCL5 from astrocytes, which subsequently triggers the release of CCL2 thereby enhancing the recruitment and activation of macrophages/microglia (El-Hage et al. 2008a) (Fig. 1). This is caused by the morphine-dependent exacerbation of Tat-induced increases in intracellular calcium concentration ([Ca2+]i) in astroglia (El-Hage et al. 2005), which accelerates the trafficking of NF-κB p65 (RelA) subunits to the nucleus and sustained CCL2, CCL5, and IL-6 transcription in astrocytes (El-Hage et al. 2008b).
Fig. 1 Opioids exacerbate HIV-1-induced CNS inflammation, in part, by augmenting CCL5-dependent increases in CCL2—key sites of opioid-HIV convergent interactions in glial inflammatory signaling cascades. Subpopulations of striatal glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in wildtype mice normally express CCR2 immunoreactivity (a-b; arrows), CCL2 (c; arrow), or μ-opioid receptor (MOR) (d; arrows) immunoreactivity (scale bars a-b = 25 μm; c-d = 15 μm). CCR2 deletion (−/−) significantly reduces HIV-1 Tat ± morphine-induced increases in GFAP+ astroglia (e) and F4/80+ macrophages/microglia (f) compared to wild type (+/+) mice at sites near (300 ± 100 μm) the site of Tat injection (*p < 0.05 vs. wild type mice) (see, El-Hage et al. 2006a). In wild-type mice, Tat ± morphine administration markedly increases the proportion of CCL2 immunoreactive astrocytes (g) or macrophages/microglia (h) [*p < 0.05 vs. other groups in wild-type or CCL5(−/−) mice; bp < 0.05 vs. vehicle- or Tat plus morphine-treated wild-type mice; #p < 0.05 vs. equivalent treatment in wild-type mice], while in CCL5 null mice, significant increases in CCL2 immunoreactivity were only seen in macrophages/microglia co-exposed to Tat and morphine (§p < 0.05 vs. vehicle injected CCL5 knockout mice) (see, El-Hage et al. 2008a). CCL5 expression in striatal GFAP-immunoreactive astrocytes (arrows) increases following Tat injections (i, j) compared to wild-type control mice (not shown) (El-Hage et al. 2008a). Opioids exacerbate HIV-1-induced CNS inflammation, in part, by increasing CCL5 and augmenting CCR5-dependent increases in CCL2 production by astrocytes resulting in the activation and recruitment of microglia/macrophages and spiraling inflammation (k). Additional factors likely mediate the proinflammatory cascade, but these are less well substantiated (?). Moreover, autocrine and reciprocal paracrine (astroglial ↔ macrophage/microglial) intercellular, feedback amplification mechanisms from macrophages/microglia are likely to be operative (dashed red arrow) (also see, Kang and Hebert 2011) and occur elsewhere within the cascade (not shown); effects of HIV-1 Tat/HIV, red arrows; sites of opioid convergence, blue arrows; pro-BDNF:mature BDNF (mBDNF) ratio (Kim et al. 2018). (a-f) Modified and reprinted with permission from El-Hage et al. (2006a). (g-k) Modified and reprinted with permission from El-Hage et al. (2008a)