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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-year old puzzle as to how Amitriptyline functions as a pain reliever: Mechanistic insights into how Amitriptyline functions as a pain medication: Amitriptyline (trade name: Elatrol, Elatrolet, Elavil, Endep, Fiorda, Laroxyl, Latilin, Levate and others), used in the treatment for major depressive order, and anxiety disorders, prevention of migraines, fibromyalgia, postherpetic neuralgia, and insomnia,  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, 12/July/2019, 11.29 pm


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:

Antidepressant Amitriptyline is prescribed for the treatment of major depressive disorder and anxiety disorders, prevention of migraines, fibromyalgia and postherpetic neuralgia, insomnia, and others,  all over the world, for over sixty-years. However, the mechanistic basis of its therapeutic effect, in attenuating various kinds of pain, remains largely unknown up until now. This study provides, for the first time, mechanistic insights into how commonly used Amitriptyline may attenuate pain, low back pain, headache, migraine, and trauma.

A therapeutic mix encompassing Amitriptyline, 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 Amitriptyline inhibits acute and chronic pain.  A pharmaceutical mixture encompassing Amitriptyline 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. Amitriptyline functions as an analgesic medication through induction of PD-L1, and down regulation of Cox-2, TRPV1 and CGPR.

Figure 3. Amitriptyline 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 known antidepressant Amitriptyline attenuates acute and chronic pain and trauma, through up regulation of PD-L1.

Figure 4. While antidepressant low-dose Amitriptyline (25mg/day) has been shown to attenuate chronic low back pain    (without a clearly proven mechanism of action however), this study suggests, for the first time, that Amitriptyline attenuates chronic low back pain, headaches, acute and chronic pain and trauma, through down regulation of Cox-2 and others, and up regulation of PD-L1.

Thus, a pharmacological mixture encompassing Amitriptyline or its analogs, either alone or in combination with other drugs, can be used to treat acute and chronic pain and trauma.

Given: (1) the mechanistic basis as to how Amitriptyline (fig.1) may aid in attenuating or decreasing or alleviating short- and long-term pain, low back pain, headache, migraine, and trauma; and (2) that Amitriptyline is largely side-effect free, unlike most of analgesics available in the market, which ‘re experimentally proven to be liver toxic, in larger doses, physicians/orthopedicians/pain therapists may consider either prescribing Amitriptyline to the needy patients or put this interesting observation into a clinical trial.

Together, this study suggests, for the first time, with detailed mechanistic insights,  that  Amitriptyline can be prescribed for patients suffering from short- and long-term pain, low back pain, headache, migraine and trauma (Figure 2-4).


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 Amitriptyline increase the expression of PD-L1?

# Research cooperation


References:

Citation: Boominathan, L., Solving a sixty-year old puzzle as to how Amitriptyline functions as a pain reliever: Mechanistic insights into how Amitriptyline functions as a pain medication: Amitriptyline (trade name: Elatrol, Elatrolet, Elavil, Endep, Fiorda, Laroxyl, Latilin, Levate and others), used in the treatment for major depressive order, and anxiety disorders, prevention of migraines, fibromyalgia, postherpetic neuralgia, and insomnia,  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, 12/July/2019, 11.29 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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

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