Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Zhang, Li; Zhang, Jiangtao; Hang, Li-Hua; Liu, Tong

doi:10.3389/fphar.2020.01078

Cited by 47 publications

(63 citation statements)

References 78 publications

(115 reference statements)

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“…We subsequently explored that possible role of opioid receptors in low-dose formalin-induced itch in mice. Opioid receptors can be divided into three classes: μ-, κ-, and δ-opioid receptors, which are distributed in the central nervous system (CNS) and peripheral nervous system (PNS) ( 39 ). It has been reported that μ-opioid receptor agonists evoke itch, while κ-opioid receptor agonists inhibit itch in both animal models and human ( 40 ).…”

Section: Resultsmentioning

confidence: 99%

Formalin Itch Test: Low-Dose Formalin Induces Histamine-Independent, TRPA1-Mediated Itch in Mice

Zhang

et al. 2021

Front. Med.

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Chronic itch is a common distressing symptom of many diseases, which reduced patient's quality of life. The mechanistic study on itch and screening for new anti-itch drugs require the development of new pre-clinical itch animal models. Herein, we established an acute itch model by intradermal (i.d.) injection of low-dose formalin into the neck or cheek in mice. In mice, i.d. injection of formalin (0.1–5%) in the nape of the neck evoked robust scratching behavior in a dose-dependent manner and the dose–response curves showed an inverted “U” shape. I.d. injection of formalin (0.3–0.6%) into the cheek evoked scratching in mice but wiping in rats, while formalin (1.25–5%) induced mixed wiping and scratching behavior in both mice and rats. Further, we found that 0.3% formalin-induced scratching was histamine-independent and significantly attenuated by transient receptor potential ion channel A1 (TRPA1) inhibitor (HC030031) or in TRPA1 knockout (KO) mice, but not affected by transient receptor potential ion channel V1 (TRPV1) inhibitor (capsazepine) or in TRPV1 KO mice. Additionally, 0.3% formalin-induced up-regulation of phosphorylation of extracellular regulated protein kinases (p-ERK) in the dorsal root ganglion (DRG) and scratching were suppressed by intrathecal injection of MEK inhibitor U0126 in mice. Incubation of 0.03% formalin induced the accumulation of intracellular reactive oxygen species (ROS) in the cultured DRG-derived cell line ND7-23, and formalin-induced itch was suppressed by antioxidants in mice. Finally, perfusion of 0.03% formalin induced elevation of intracellular calcium in a subset of primary cultured DRG neurons of mice. Thus, these results indicate that low-dose formalin induced non-histaminergic itch by activation of TRPA1 in mice, which may be employed as a useful acute itch model for screening potential anti-itch drugs.

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Section: Resultsmentioning

confidence: 99%

Formalin Itch Test: Low-Dose Formalin Induces Histamine-Independent, TRPA1-Mediated Itch in Mice

Zhang

et al. 2021

Front. Med.

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“…Opioids have their side-effects and development of targeted opioid drugs for Mu receptor heterodimers is an opportunity for research in times to come. [ 37 ]…”

Section: Pandemic Woesmentioning

confidence: 99%

Onco-Anaesthesiology and palliative medicine: Opportunities and challenges

et al. 2021

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Global cancer burden is on the rise and many more patients present for surgery or other oncological diagnostic or therapeutic interventions requiring anaesthesia. Oncology therapy is unique as it requires a multidisciplinary team of surgical, medical and radiation oncologists apart from palliative medicine (PM) specialists, and anaesthesiologists. Anaesthetic management can affect the outcome of oncology treatment both by ensuring early return to oncology treatment and some anaesthetic techniques being innately associated with recurrence. Hence, the time has come for a separate super-speciality of onco-anaesthesiology to cater to the complex unmet needs of cancer patients. PM is the fourth dimension of oncology care and so mandatory education and training should be included in the undergraduate curriculum.

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“…Gαq subunit activates phospholipase C to produce inositol trisphosphate and diacylglycerol for the phosphorylation of protein kinase C (PKC) [ 22 , 23 ]. Gαi/o subunit inhibits the adenylate cyclase for producing cyclic adenosine monophosphate, which inactivates protein kinase A (PKA) [ 23 , 25 ]. Morphine and DAMGO further mediate MAPKs activation that has been directly verified by the use of its signaling inhibitors, such as PKC or PKA inhibitors, in MOR-dependent signaling [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…To date, mechanisms of receptor interactions between OR and OR/other classes of GPCRs give the hypothesis of cross-talk that occurs in heterodimer formation, heterologous desensitization and intracellular signaling [ 24 , 25 , 26 , 27 , 28 , 29 ]. For example, CYM51010, a MOR-DOR-biased agonist, increases co-expression of MOR and DOR in injured DRG neurons and has analgesic effects on neuropathic pain by subcutaneous administration [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Cross-Talk of Toll-Like Receptor 5 and Mu-Opioid Receptor Attenuates Chronic Constriction Injury-Induced Mechanical Hyperalgesia through a Protein Kinase C Alpha-Dependent Signaling

Chang

Liu

Yeh

et al. 2021

IJMS

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Recently, Toll-like receptors (TLRs), a family of pattern recognition receptors, are reported as potential modulators for neuropathic pain; however, the desired mechanism is still unexplained. Here, we operated on the sciatic nerve to establish a pre-clinical rodent model of chronic constriction injury (CCI) in Sprague-Dawley rats, which were assigned into CCI and Decompression groups randomly. In Decompression group, the rats were performed with nerve decompression at post-operative week 4. Mechanical hyperalgesia and mechanical allodynia were obviously attenuated after a month. Toll-like receptor 5 (TLR5)-immunoreactive (ir) expression increased in dorsal horn, particularly in the inner part of lamina II. Additionally, substance P (SP) and isolectin B4 (IB4)-ir expressions, rather than calcitonin-gene-related peptide (CGRP)-ir expression, increased in their distinct laminae. Double immunofluorescence proved that increased TLR5-ir expression was co-expressed mainly with IB4-ir expression. Through an intrathecal administration with FLA-ST Ultrapure (a TLR5 agonist, purified flagellin from Salmonella Typhimurium, only the CCI-induced mechanical hyperalgesia was attenuated dose-dependently. Moreover, we confirmed that mu-opioid receptor (MOR) and phospho-protein kinase Cα (pPKCα)-ir expressions but not phospho-protein kinase A RII (pPKA RII)-ir expression, increased in lamina II, where they mostly co-expressed with IB4-ir expression. Go 6976, a potent protein kinase C inhibitor, effectively reversed the FLA-ST Ultrapure- or DAMGO-mediated attenuated trend towards mechanical hyperalgesia by an intrathecal administration in CCI rats. In summary, our current findings suggest that nerve decompression improves CCI-induced mechanical hyperalgesia that might be through the cross-talk of TLR5 and MOR in a PKCα-dependent manner, which opens a novel opportunity for the development of analgesic therapeutics in neuropathic pain.

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Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Cited by 47 publications

References 78 publications

Formalin Itch Test: Low-Dose Formalin Induces Histamine-Independent, TRPA1-Mediated Itch in Mice

Formalin Itch Test: Low-Dose Formalin Induces Histamine-Independent, TRPA1-Mediated Itch in Mice

Onco-Anaesthesiology and palliative medicine: Opportunities and challenges

Cross-Talk of Toll-Like Receptor 5 and Mu-Opioid Receptor Attenuates Chronic Constriction Injury-Induced Mechanical Hyperalgesia through a Protein Kinase C Alpha-Dependent Signaling

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