PAIN;
TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain.
Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated.
https://www.pnas.org/doi/10.1073/pnas.1715972115
Functional and biochemical interaction between PPARα receptors and TRPV1 channels: Potential role in PPARα agonists-mediated analgesia.
Collectively, these results provide evidence for a PPARα-mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARα agonists in vivo. https://pubmed.ncbi.nlm.nih.gov/25014183/ administration of PPAR ligands reduces inflammatory pain and neuropathic pain.
https://pubmed.ncbi.nlm.nih.gov/19607969/
Palmitoylethanolamide which activates PPAR-a was used successfully for chronic and neuropathic pain and inflammation, as demonstrated in clinical trials (and further may have benefits with ME/CFS). These include peripheral neuropathies such as diabetic neuropathy, chemotherapy-induced peripheral neuropathy, carpal tunnel syndrome, sciatic pain, osteoarthritis, low-back pain, failed back surgery syndrome, dental pains, neuropathic pain in stroke and multiple sclerosis, chronic pelvic pain, postherpetic neuralgia, and vaginal pains.
https://pubmed.ncbi.nlm.nih.gov/23166447/
Life extension mentioned it also as safer pain alternative
https://www.lifeextension.com/magazine/2019/3/turn-off-the-pain-signal https://www.lifeextension.com/magazine/2022/9/turn-off-pain-signals
TNFalpha may have a significant impact on nociceptive signaling at the spinal cord level that could be mediated by increased responsiveness of presynaptic TRPV1 receptors to endogenous agonists.
https://pubmed.ncbi.nlm.nih.gov/20796308/ and
https://pubmed.ncbi.nlm.nih.gov/22189061/ TNF-α could sensitize TRPV1 by promoting its expression, inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840530/
TRPV1 sensitization was maintained by 5-HT/5-HT3A.
https://pubmed.ncbi.nlm.nih.gov/31708101/
CB1-cannabinoid-, TRPV1-vanilloid- and NMDA-glutamatergic-receptor-signalling systems interact in the prelimbic cerebral cortex to control neuropathic pain symptoms
https://www.sciencedirect.com/science/article/abs/pii/S0361923020306353 Targeting the Glutamate NMDA receptor subunit NR2B for the treatment of neuropathic pain
https://pubmed.ncbi.nlm.nih.gov/19789073/
vitamin D may act as a partial TRPV1 agonist that may promote a small but sustained calcium influx into cells without initiating calcium-induced desensitization. Conversely, vitamin D can also act as an antagonist in the presence of a full agonist, therefore decreasing TRPV1-mediated calcium influx and may act to oppose excessive calcium influx and over-activation of calcium-dependent cellular signaling. This dual function of vitamin D on TRPV1 activity may provide an elegant means to not only generate a tonic basal calcium signal but also prevent over-activation or calcium-induced damage in the presence of a full agonist. (it can limit overexpression by a different activator of TRPV1)
https://pmc.ncbi.nlm.nih.gov/articles/PMC8032246/
Mutations in these genes, such as SCN9A, SHANK3, and CNTNAP2, lead to altered neuronal function that produce different responses to pain, shown in both mouse and human models.
https://pubmed.ncbi.nlm.nih.gov/33987518/
SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons. Homozygous and heterozygous Shank3 complete knockout results in impaired heat hyperalgesia in inflammatory and neuropathic pain. TRPV1 modulates glutamate release from nociceptor afferents in the spinal cord, and the authors found that loss of SHANK3 impaired this function. loss of SHANK3 impairs TRPV1 signalling in human neurons. Biochemical experiments showed that SHANK3 and TRPV1 can physically interact and that SHANK3 regulates the surface expression and trafficking of TRPV1 in cell culture. Further analysis showed that the proline-rich domain of SHANK3 is responsible for mediating these interactions and regulating TRPV1 function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182147/
Since SHANK3 is concentrated in glutamatergic synapses, it interacts with all prominent glutamate receptors, such as NMDA, AMPA, and mGlu receptors. SHANK3 also indirectly interacts with Neuroligins (NLGN), a family of post-synaptic adhesion molecules. Most of these interactions are indirect and mediated by post-synaptic proteins such as GKAP, Homer PSD95 etc. InsG3680 Shank3 mutant mice show disruptions of glutamatergic signaling as compared to WT controls.
https://www.nature.com/articles/s41398-021-01612-3
Specific deletion of Shank3 in Sodium Nav1.8-expressing sensory neurons also impairs heat hyperalgesia in homozygous and heterozygous mice. Human genetics strongly suggests that SCN9A, the human gene encoding sodium channel subunit Nav1.7, critically regulates pain sensitivity Interestingly, transient sodium currents, as well as Nav1.7-mediated sodium currents (isolated by Protoxin-II) were normal in Shank3-deficient DRG neurons compared with WT neurons. Neither did we find changes in neuronal excitability in Shank3−/− mice: Shank3-deficient neurons and WT neurons fired action potentials at the same rate. Thus, sodium channels such as Nav1.7 may not contribute to pain defects in Shank3−/− mice.
https://www.nature.com/articles/nrn.2016.179
Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Nav1.7, 1.8 and 1.9 can cause pain, while loss of function Nav1.7 mutations lead to loss of pain in otherwise normal people.
https://pubmed.ncbi.nlm.nih.gov/26941184/
SCN9A The human SCN9A gene encodes the pore-forming subunit of Nav1.7, a voltage-gated sodium channel. The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. NaV1.7 sodium channels are found in nerve cells called nociceptors that transmit pain signals. Nociceptors are part of the peripheral nervous system, which connects the brain and spinal cord to cells that detect sensations such as touch, smell, and pain. Nociceptors are primarily involved in transmitting pain signals. The centers of nociceptors, known as the cell bodies, are located in a part of the spinal cord called the dorsal root ganglion. Fibers called axons extend from the cell bodies, reaching throughout the body to receive sensory information. Axons transmit the information back to the dorsal root ganglion, which then sends it to the brain. NaV1.7 sodium channels are also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain.
Mutations in SCN9A channels have been linked to several inherited diseases including erythromelalgia (vasodilation with burning pain), paroxysmal extreme pain disorder, and congenital indifference to pain). Nav1.7, upregulated in prostatic cancer and inflammation, is a cancer biomarker and a therapeutic target in treatment of pain. loss-of-function mutations are linked to complete insensitivity to pain that may be accompanied by anosmia. Other gain-of-function variants in NaV1.7 are risk factors for painful small-fibre neuropathy.
https://www.nature.com/articles/nrn3404/
Shank3 levels are also lowered via zinc deficiency that regulates Shank levels as well as NLRP3 over activation as being discussed in relation to ME/CFS.
https://forums.phoenixrising.me/thr...ic-fatigue-syndrome.90582/page-3#post-2442240
