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Mohan Interleukin-1beta: a common thread

astrocytes become activated in OIH. [5] condition. Recent data has shown that prolonged
treatment with morphine doubled the duration of pain
Long-term potentiation (LTP) is a sensitization of associate with nerve injury independent of opioid-
synapse (homo- and heterosynaptic) that enhances receptor selectivity. Morphine-mediated persistence
[21]
the strength of the synapse and its signal transduction. of pain was attenuated following co-administration
Increase LTP can cause hypersensitivity and may lead with the IL-1 receptor antagonist (IL-1ra). Prolonged
[21]
to hyperalgesia and has been shown to be involved morphine use can activate glial toll-like receptors such
in OIH. In addition to glutamate-NMDA receptor as the toll-like receptor 4 (TLR4) which following priming
[6]
mediated LTP in OIH, glial cells and released pro- ensures neurotoxicity, immune mediated amplification
inflammatory mediator have also been implicated in of nociceptive signaling in the spinal cord. [5,21-23]
LTP in OIH. For example, cytokines interleukin-1beta Evidence has also shown that morphine can directly
(IL-1β) and tumor necrosis factor-α (TNF-α) can compromise opioid-induced analgesia by promoting
enhance post-synaptic potentials leading to neuronal proinflammation via a TLR4 dependent mechanism
excitation in the spinal cord. Cytokines in the central and can potentiate mechanical allodynia. [24,25]
nervous system act mostly through the activation of
glial cells to induce the release of other mediators Reactive microglia has been implicated in playing a key
that trigger LTP and hyperexcitability or neurons that role in morphine-mediated persistent pain conditions
leads to OIH. The pro-inflammatory cytokine, IL-1β as demonstrated with the use of glial cell blockers. [26-29]
[7]
plays a major role in host defense and inflammation It is noteworthy that while there are many reports that
and is associated with inflammatory pain and opioid have described the importance of neuroinflammation in
analgesia. In rodent models, peripheral administration analgesic tolerance, since 2002 only a dozen few have
of IL-1β produced hyperalgesia and reduced morphine focused on immune mechanism for OIH with four of
analgesia while contributing to morphine tolerance. [8,9] the studies showing that the blockade of IL-1β reduced
At the molecular level, the interaction of IL-1β and OIH. [30-33] In astrocytes, morphine exposure has
the opioid system is shown by the finding that IL-1β shown to trigger astrocytes activation and lead to the
increased the levels of mu opioid receptor (MOR) upregulation of IL-1β. Also, more recently, ultra-low
[34]
mRNA in primary astrocytes, neurons and in neural dose morphine induced OIH was found to selectively
microvascular endothelial cells. [10-12] Other cytokines, activate astrocytes. Together, this indicates that
[35]
including IFNα, TNFα, IL-4 and IL-6, also increase concurrent activation of microglia and astrocytes are
the expression of MOR in neuroblastoma cells and involved in OIH.
peripheral immune cells. [13-15] These results and others
show that cytokines interact with endogenous opioid In conclusion, my hypothesis is that opioid tolerance
systems but explicit molecular mechanisms remain is a consequence of OIH. The increase in pain
elusive. Interleukin-1beta mediates its effects through sensitivity caused by OIH masks opioid analgesia and
the interleukin-1 receptor type 1 (IL1R1) protein, which if this continues would lead to opioid tolerance. At the
is a member of the Toll-like/IL-1R1 (TIR) domain family molecular level, increased, chronic use of opioids would
of membrane receptors. Like the Toll-like receptors, cause a decrease in MOR expression contributing to a
[16]
the IL1R1 receptor signals through a complex of loss of any analgesia mediated by opioids. Therefore,
accessory proteins and downstream signaling events in the future it would be key to determine the cellular
including activation of the JAK-STAT, MAPK, and chronological order involved in increasing synaptic
NF-κB pathways. Functional studies in cell lines activity (i.e. LTP), which is normally mediated by
[17]
show that transcription factors from the JAK-STAT, increased levels of glutamate in the synaptic cleft
MAPK and NF-κB signaling pathways alter MOR gene and is removed by astrocytes. Current research
transcription after cytokine stimulation. [10,18,19] shows that the common thread that may lead to OIH
is the pro-inflammatory cytokine, IL-1β. Morphine
The NOD-like receptor protein 3 (NLRP3) inflammasome alone can increase the expression and release of
and downstream release of IL-1β are involved in pain IL-1β from activated microglia and this increase may
conditions such as post-operative pain, post-herpetic disrupt glutamate homeostasis. Recent evidence has
neuralgia, diabetic peripheral neuropathy and spinal shown that IL-1β can down-regulate the expression
cord injury and if not controlled can lead to neuropathic of GLT-1 and directly elevate the levels of glutamate
pain. In these and other forms of pain conditions, and trigger the release of ATP from glia. Increased
[21]
[20]
opioid such as morphine remains the gold standard glutamate, ATP and reactive oxygen species may
analgesic and opioid use for pain management has contribute to excitotoxicity and chronic inflammatory
dramatically increased, with little assessment of and therefore the cycle may continue until morphine is
the pathological consequences on the primary pain discontinued. Current and previous data supports the
202 Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ September 26, 2016