Solving a sixty plus year of puzzle as to how Dexamethasone functions as a pain reliever: Mechanistic insights into how Dexamethasone functions as an analgesic agent: Dexamethasone (trade name: Boycadron, Decadron, Dexasone, Diodex, hexadrol, maxidex 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, 24/September/2019, 11.45 am

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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 sixty plus year of puzzle as to how Dexamethasone functions as a pain reliever: Mechanistic insights into how Dexamethasone functions as an analgesic agent: Dexamethasone (trade name: Boycadron, Decadron, Dexasone, Diodex, hexadrol, maxidex 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:

Dexamethasone is one of the most used corticosteroids for a number of disease conditions, including arthritis, breathing problems, asthma, COPD, server allergies, skin and eye diseases,  preterm labor, inflammation, pain and others. ‘It is also one of the most prescribed medication, with 1 million+ used in the US.  Though Dexamethasone is in use for over sixty 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 Dexamethasone may attenuate pain, lower back pain, headache, migraine, and trauma.

Dexamethasone (Brand names:   Decadron, Dexasone, Diodex, hexadrol, and  maxidex 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).

Figure 1.Mechanistic insights into how Dexamethasone inhibits acute and chronic pain.  A pharmaceutical mixture encompassing Dexamethasone enhances PD-L1, while decreasing Cox-2 & TRPV1 levels. Thereby, it suppresses thermal and mechanical hypersensitivity, phosphorylates SHP-1, inhibits activation of sodium channels, alleviates nociceptive neuron excitability, attenuates acute and chronic pain, low back pain, headaches, and migraine.

Figure 2. Dexamethasone (Decadron, Dexasone, Diodex, hexadrol, and  maxidex) functions as an analgesic medication through induction of PD-L1, and down regulation of Cox-2, TRPV1 and CGPR. One may visit the above link (https://knowledgeplus.nejm.org/question-of-week/1783/) to find a case presentation where dexamethosone is the drug of choice for the treatment of pain.

Figure 3. Dexamethasone attenuates acute and chronic pain and trauma through down regulation of Cox-2, TRPV1, CGPR and others, and up regulation of PD-L1.

Figure 4. While pharmacological activation of PD-L1 has been shown to attenuate acute and chronic pain, this study suggests that  Dexamethasone attenuates acute and chronic pain and chronic lower back pain, through up regulation of PD-L1 and others.

Thus, a pharmacological mixture encompassing Dexamethasone 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 Dexamethasone (fig.1) may aid in preterm labor, in alleviating short- and long-term pain, lower back pain,  migraine, and trauma, Physicians/Orthopedicians/Pain therapists/Anesthesiologists/Primary Care and Interventional Pain Physicians/researchers may consider taking up this interesting observation for experimental study, 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 Dexamethasone increase the expression of PD-L1 and attenuate the expression of  Cox-2, TRPV1, and CGPR?

# Research cooperation


References:

Citation: Boominathan, L., Solving a sixty plus year of puzzle as to how Dexamethasone functions as a pain reliever: Mechanistic insights into how Dexamethasone functions as an analgesic agent: Dexamethasone (trade name: Boycadron, Decadron, Dexasone, Diodex, hexadrol, maxidex 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, 24/September/2019, 11.45 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

Web: http://genomediscovery.org or http://newbioideas.com

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