Introduction:What they say:
A recent study from Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China; and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, US shows that “PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1.” This study was published, in the 22 May 2017 issue of Nature Neuroscience (one of the best journals in Neurobiology with an impact factor of 16.724+), by Prof Ru-Rong Ji, Chen G and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, the Director-cum-chief Scientist of GBMD, reports that: Solving a fifty plus year puzzle as to how labor pain relief medication Fentanyl functions as a pain reliever: Mechanistic insights into how Pethidine functions as an analgesic agent: Fentanyl (trade name: Actiq, Duragesic, Fentora, Sublimaze and others), used to treat moderate to severe pain during labor and delivery, in post-operative pain management, in chronic cancer pain management and in others, increases the expression of PD-L1, decreases the expression of Cox-2, TRPV1, and CGPR, attenuates acutes and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene
What is known?
It has recently been shown that blocking PD-1 with antibodies one could make tumors shrink. This work, relating to Cancer immunotherapy, has been chosen as Science’s breakthrough of the year. However, the work published recently, which is described below, may highlight the caveat in such an approach, as blocking PD-L1 may promote spontaneous pain and allodynia in cancer-bearing mice.
Prof. Ji has shown recently that: (1) Programmed cell death ligand-1 (PD-L1), produced by melanoma and normal neural tissues, inhibits acute and chronic pain; (2) injection of PD-L1 alleviates pain, and thereby functions as an analgesic agent; (3) Neutralization of PD-L1 or Block of PD1 promotes mechanical allodynia (hypersensitivity to pain); (4) PD1 null mice suffer from thermal and mechanical hypersensitivity; (5) PD-L1 promotes phosphorylation of SHP-1 and inhibits Sodium channels via PD-1 activation; and (6) PD-L1 inhibits nociceptive neuron excitability in dorsal root ganglion and thereby functions as a neuromodulator, suggesting that increasing the expression or the level of PD-L1/PD1 may alleviate pain and thermal and mechanical hypersensitivity.
From research findings to therapeutic opportunity:
Fentanyl is the most used synthetic opioid pain medication. It is used to treat moderate to severe pain during labor and delivery. Fentanyl transdermal patches are used to treat cancer pain and in the management of chronic cancer pain. ‘It is one of the most prescribed medication. Though Fentanyl is in use for over fifty years, the mechanistic basis of its therapeutic effect, in attenuating various kinds of pain and pain sensation, including lower back pain,remains largely unknown up until now. This study provides, for the first time, mechanistic insights into how commonly used Fentanyl may attenuate pain, lower back pain, headache, migraine, and trauma.
Fentanyl (brand names: Actiq, Duragesic, Fentora, Sublimaze and others), by increasing the expression of its target genes, it increases PD-L1; and decreases Cox-2 (Cyclooxygenase-2) , TRPV1 (transient receptor potential vanilloid 1) and CGPR (Calcitonin gene-related peptide) levels (fig. 1). Thereby, it: (a) inhibits acute and chronic pain and trauma; (b) alleviates thermal and mechanical hypersensitivity; (c) activates signal transduction cascade downstream of PD-1 receptor; (c) phosphorylates SHP-1; (d) inhibits sodium channels and nociceptive neuron excitability (Fig 2-4).
Thus, a pharmacological mixture encompassing “Fentanyl or its analogs, either alone or in combination with other drugs, can be used to treat labor/delivery pain, acute and chronic pain, lower back pain, migraine and trauma.
Given the evidence-based mechanistic reasoning as to how Fentanyl (fig.1) may aid in attenuating or decreasing or alleviating labor/delivery pain, short- and long-term pain, lower back pain, migraine, and trauma, obstetrician-gynecologists/physicians/orthopedicians/pain therapists may consider putting this interesting observation into a clinical trial, for a further exploration of its mechanism of action.
Details of the research findings:
Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.
Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/
Amount: $1, 500#
Undisclosed mechanistic information: How does Fentanyl increase the expression of PD-L1 and attenuate the expression of Cox-2, TRPV1, and CGPR?
# Research cooperation
Citation: Boominathan, L., Solving a fifty plus year puzzle as to how labor pain relief medication Fentanyl functions as a pain reliever: Mechanistic insights into how Fentanyl functions as an analgesic agent: Fentanyl (trade name: Actiq, Duragesic, Fentora, Sublimaze and others), used to treat moderate to severe pain during labor and delivery, in post-operative pain management, in chronic cancer pain management and in others, increases the expression of PD-L1, decreases the expression of Cox-2, TRPV1, and CGPR, attenuates acutes and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene, 31/July/2019, 8.08 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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