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].