Preclinical studies indicate opioid-induced neuroimmune signaling alter the saliency of opioid reward and physical dependence (Narita et al. 2006; Hutchinson et al. 2008, 2009). Direct injections of astrocyte-conditioned medium containing cytokines into the nucleus accumbens (NAc) increase morphine conditioned place preference (Narita et al. 2006). Drugs reported to selectively attenuate glial inflammation block morphine conditioned place preference and attenuate symptoms of opioid withdrawal (Narita et al. 2006; Hutchinson et al. 2009; Liu et al. 2010). μ (MOR), δ (DOR), and κ (KOR) opioid receptors are expressed by subsets of astrocytes and microglia (Stiene-Martin and Hauser 1991; Eriksson et al. 1992; Stiene-Martin et al. 1993; Ruzicka et al. 1995; Gurwell et al. 1993; Hauser et al. 1996; Turchan-Cholewo et al. 2008; Maduna et al. 2018) and are involved in opioid tolerance and dependence to varying degrees (Kieffer and Gaveriaux-Ruff 2002; Berger and Whistler 2010; Morgan and Christie 2011). Despite some reports of morphine triggering immune activation via Toll-like receptor 4 (TLR4) (Terashvili et al. 2008; Hutchinson et al. 2010; Coller and Hutchinson 2012; Hutchinson et al. 2012; Theberge et al. 2013; Lacagnina et al. 2017) by binding to a myeloid differentiation protein-2 intermediary (Wang et al. 2012), this is contrary to the typical actions of opiates, which by themselves (and in the absence of a priming event such as HIV co-exposure) tend to suppress immune function (Eisenstein 2019). A vast majority of the immune, antinociceptive, and other physiological effects of opioids are mediated by opioid receptors per se and not TLR4 (Hu et al. 2011; Fukagawa et al. 2013; Stevens et al. 2013; Mattioli et al. 2014; Eisenstein 2019).