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Gene & Protein in Disease MOR in cancer

In the pathophysiology of tumor, cancer cells from 2.1. Mu-opioid receptor
the primary tumor will spread to distal tissues and form MOR can be divided into three subtypes (MOR1, MOR2,
new tumor colonies, and it is a well-known fact that and MOR3) and activated by a variety of synthetic
cancer metastasis has become the main reason for the compounds, such as morphine, and endogenous
high mortality rate of cancer [12,13] . Cancer metastasis opioid ligands, including endorphins, enkephalins,
involves a variety of cellular mechanisms, including local and dynorphins [43,44] . MOR is widely distributed in the
invasion of cancer cells in the primary tumor, entry into central and peripheral nervous systems, and it affects
the tumor vasculature, stagnation in distal capillaries, the physiological function of neurons when activated,
extravasation into the parenchyma of target organs for thereby producing both analgesic effects and adverse
metastatic colonization, evasion of immune surveillance, effects, such as respiratory depression, nausea, vomiting,
and regulation of tissue microenvironment [14-17] . Recently, constipation, and addiction [45-47] . Moreover, it can inhibit
clinicians have found that opioids and mu (µ)-opioid the occurrence of immune and inflammatory responses,
receptor (MOR) could affect tumorigenesis and tumor which are associated with tumor vascular endothelial cell
development when used to treat acute and chronic pain in proliferation . MOR is also expressed in other cells, such
[48]
cancer patients [18,19] .
as lymphocytes, macrophages, pancreatic endocrine cells,
2. Mu-opioid receptor and its functions and gastrointestinal secretory cells, where it could regulate
inflammation, glucose metabolism, and gastrointestinal
Opioids are a class of alkaloids extracted from the opium motility (Figure 1) [48-50] .
poppy, including morphine, codeine, etc. Opioids have long
been considered one of the most effective drugs for treating MOR exhibits bidirectional effects during tumorigenesis
[51]
pain, including acute severe pain and chronic pain [20-22] . and tumor development , and many studies have shown
In 1975, Hughes et al. discovered two endogenous that opioids induce tumor angiogenesis and tumor
[23]
biopeptides with potent opioid activity in the human brain. cell growth by stimulating the MOR, thus promoting
[52,53]
Opioids and endogenous opioid peptides work by binding metastasis . However, there are studies that have
to specific protein receptors (opioid receptors). suggested that MOR induces an opposite effect in other
cancer cells. MOR overexpression has shown to promote
Opioid receptors are mainly distributed in the central tumor growth and metastasis in human liver cancer and
and peripheral nervous systems , and their activation laryngeal cancer [54,55] . The expression of MOR and related
[24]
could produce peripherally or both peripherally and drug research are topics of interest in opioid research,
centrally mediated effects, such as decreased visceral especially the relationship between MOR and tumor
smooth muscle peristalsis, pupil narrowing, lethargy, recurrence and metastasis. At present, MOR agonists
clouding of consciousness, and respiratory depression [25-28] . and antagonists have been shown to inhibit cancer
Opioids in the central nervous system (CNS) could lead to cell proliferation and used in combination with tumor
changes associated with hyperalgesia and sensitization [29-31] . molecule-targeting drugs to delay tumor progression [51,56] .
Moreover, the activation of the opioid system in other CNS KOR and DOR are mainly distributed in the peripheral
pathways may modulate emotions, including irritability sensory neurons and spinal cord, and they are involved
and euphoria [32,33] . in analgesia. MOR, KOR, and DOR can be activated by
The opioid receptor is a G protein-coupled receptor endogenous peptides, such as endorphins, enkephalins,
(GPCR) located in the cell membrane, cytoplasm, or and dynorphins. They could be triggered by other synthetic
[43]
nucleus and is one of the most abundant class of cell or semi-synthetic small molecule ligands exogenously .
membrane surface receptors . This receptor is an 2.2. Pain control
[34]
important drug target for pain management, addiction,
and emotion regulation, including MOR, kappa (κ)-opioid The analgesic effect of morphine is primarily mediated
receptor (KOR), delta (δ)-opioid receptor (DOR), and by MOR (Figure 2) . MOR is widely expressed in many
[57]
nociceptive peptide opioid receptor, each of which is pain-related brain regions, including the periaqueductal
divided into several subtypes [35,36] . MOR, KOR, and DOR gray, thalamus, rostral ventromedial medulla, and anterior
are widely distributed in the brain, brainstem downlink cingulate cortex, in addition to the spinal cord and primary
pathways, and dorsal horn of the spinal cord in the CNS sensory neurons [58-61] . The mechanisms underlying the
and are present peripherally in the heart, digestive tract, analgesic effect are as follows: MOR is activated and then
and immune system [37-40] . Endogenous pain-sensitive decoupled from the heterotrimeric inhibitory G protein
peptides, the fourth member of the opioid receptor family, (Gi), which promotes the influx of sodium ion (Na ) and
+
are known as opioid receptor-like 1 (ORL1), which have calcium ion (Ca ) as well as the inflow of potassium ion (K )
+
2+
been successfully isolated by Mollereau et al. [41,42] . through cyclic adenosine monophosphate/protein kinase
Volume 2 Issue 2 (2023) 2 https://doi.org/10.36922/gpd.282