4.1 Opioids
Opioids are effective in activating all subtypes of opioid receptors (i.e., μ, δ, and κ). The activation of μ-opioid receptors expressed on ventral tegmental area neurons is primarily associated with the acute potentiating effects of opioids[34]. There is evidence that opioids alter immune signaling through combining the pattern recognition receptor Toll-like receptor 4 (TLR4) with the TLR4 coreceptor myeloid differentiation factor 2[35, 36].
Opioid addiction affects many physiological functions, including the response of the immune system. At present, clinical studies have confirmed the changes of its related interleukin family factors. Some teams found that compared to healthy people, opioid users showed a significant increase in the production of related factors such as pro-inflammatory factors IL-1β and IL-6 in plasma[37, 38]. This change may be due to the fact that during this period, microglia generate reactive oxygen species and releases signals to recruit peripheral immune cells for inflammatory responses[39]. Peripheral blood data from other populations showed decreased interleukin IL-2 and increased IL-4, IL-10, and IL-17A[40].
Based on the literature, more recent attention has focused on IL-6. It has been shown that striatal astrocyte cultures treated with morphine display an exaggerated increase in the release of the chemokine IL-6[41]. Interestingly, opioids can essentially alter HIV pathogenesis by directly modulating immune function and directly altering the CNS response to human immunodeficiency virus (HIV), leading to an increased risk for CNS complications[42]. The IL-1 in the hippocampus is also the focus of recent research. IL-1 appears to play a key role in the memory within the hippocampus. To be specific, it can affect hippocampus-dependent memory[43]. Opioid-related environmental stimuli elicit powerful immune-altering effects by stimulating neural circuits including the basolateral amygdala and nucleus accumbens. These brain regions are known to have direct and indirect connections with the hippocampus[43]. On the one hand, heroin administration inhibits inducible hippocampal nitric oxide (NO) production. On the other hand, inhibition of IL-1β expression in the dorsal hippocampus (DH) can make the phenomenon of NO-inhibition caused by heroin disappear[43]. This results in the normalization of herd immunity in heroin users or patients exposed to opioid therapy[44, 45]. The team’s study mentions that IL-1 signaling is also involved in the acquisition of learning effects in addition to the expression of heroin-conditioned immune responses[46]. In another experiment on post-traumatic stress disorder (PTSD) in a clinical population, opioid withdrawal was speculated to produce symptoms similar to PTSD. Experimenters gave mice severe foot shocks that resulted in an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and subsequent fear learning was blocked by the DH IL-1 receptor antagonist (IL-1RA) off[47]. Another group of studies focused on interleukin-4, and examined its efficacy in protecting mice from opioid-induced behavior and toxicity by blocking IL-4 signaling. Therefore, this literature have pointed out that IL-4 has been recognized as a pharmacological target to improve the efficacy of the next generation vaccine[48]. In another study, morphine increased morphine-induced neuroinflammation by reducing the anti-inflammatory cytokine interleukin 10 (IL-10) in the nucleus accumbens[49]. In sum, these findings suggest that opioids alter neuroimmunity through several potential mechanisms[50].