Much research has been devoted to the role of TLR4 and associated signaling cascades in mediating opioid- and stimulant-related behaviors in animal models. Opioids bind to the TLR4 co-receptor, myeloid differentiation factor 2 (Hutchinson et al., 2010; Wang et al., 2012). TLR4 KO animals have impaired drug reward learning, showing attenuated CPP to cocaine, morphine, and oxycodone (Hutchinson et al., 2012) (Kashima and Grueter, 2017). However, TLR4 mutant and KO mice retain opioid-induced analgesic tolerance, hyperalgesia, and physical dependence, indicating TLR4 is not required for these effects (Mattioli et al., 2014). TLR4 inhibition with (+)-naloxone impairs CPP to morphine and cocaine, decreases opioid and cocaine self-administration, and inhibits morphine- and cocaine-induced dopamine increases in the NAc (Hutchinson et al., 2012; Northcutt et al., 2015). However, (Tanda et al., 2016) reports no effect of (+)-naloxone and (+)-naltrexone on intravenous heroin- or cocaine-induced dopamine release. In addition, (+)-naloxone does not reduce methamphetamine craving during withdrawal (Theberge et al., 2013). Similar to findings from alcohol studies, TLR4 may mediate some components of addiction to opioids and psychostimulants but may not be a primary
