Endocannabinoid deficiency and the neuropathic pain of noise hyper-sensitivity.
Ototoxicity vs CNS over-activity. Also: Post-Translational modification (PTM) of proteins. Pomegranate, CoQ10, mitochondrial support nutrients and cannabinoids may help.
Lack of endocannabinoids may be a cause of noise hypersensitivity. An overactive startle reflex may also indicate a deficiency of cannabinoids as they are needed for synaptic regulation, to inhibit nerve signals after a time lapse. Imagine a doorbell buzzing . . . what if it never stopped? or only stopped after two minutes of continual buzzing? That would likely seem painful. Prepulse inhibition (PPI) is a phrase used to describe our normal ability to dampen down a startle response if prewarned that a loud noise is about to happen. It is common in both autism (Erturk, et al, 2016) and schizophrenia to have a delayed PPI, and be over-startled, but the mechanism of action seems to be slightly different. (Madsen, et al, 2014)
Olanzapine helped improve the PPI response in schizophrenic patients. (Declan, et al, 2008, viewable at ScD) The medication reduces breakdown of cannabinoids and may cause overeating and weight gain as a side effect. Using CBD drops has been helpful for restoring a more normal startle reflex if lack of cannabinoids is involved. (Pedrazzi, et al, 2015)
Other drugs that make the PPI worse (in animal-based research), increasing a startle reaction even when a noise is expected, include: NMDA antagonists, dopamine agonists, serotonin receptor agonists. It is also seen with varied neurodevelopmental conditions and in transgenic mouse models of schizophrenia. (Pedrazzi, et al, 2015)
An influx of sodium might depolarize a nerve cell and send a nerve signal which might be perceived as pain or something else depending on the function of the cell or channel. Too much activity of a sensory signal might be perceived as sensitivity to noise or a constant ringing tinnitus that is CNS derived rather than being due to damaged Hair Cells within the inner ear as seen with ototoxicity. Reducing neuroinflammation may help reduce the pain of sound signals that continue too long, a problem seen in patients with autism and Alzheimer’s dementia. Hawthorn extract was found helpful for neuroinflammation in an animal-based stroke model, reducing cytotoxic T-cells and inflammatory cytokines. Beneficial Tregs and IL-10 levels were increased. (Elango and Devaraj, 2010) Phytonutrient preparations frequently are made with proprietary blends that may have synergistic benefits. Blends of herbs that balance any negatives within the mix is a goal for Traditional Chinese Medicinal remedies.
Post-Translational modification (PTM) of proteins.
A study on CNS hyperalgesia by Fujisawa, et al, found "post-translational modification (PTM) of proteolysis or phosphorylation" to be involved in the pain condition rather than increased mRNA expression of the three proteins that were identified. (Fujisawa, et al, 2008) Post-translational modification of proteins is also seen in autoimmune Rheumatoid arthritis. Auto-antibodies form against the modified proteins which leads to autoimmune damage to healthy proteins. Autoantibodies may also be formed in response to PTM of “carbamylation, glycosylation, glycation, acetylation, ubiquitination, proteolysis, phosphorylation and lipidation.” (Vasudevan, et al, 2021)
Nociceptive pain is considered acute, traumatic injury related, typically, while neuropathic pain may be chronic over-activity of pain signaling nerves. Post-translational modification of sodium voltage gated channels modifies their activity in neuropathic chronic pain syndrome. Inflammatory pain is caused by factors released by mast cells, neutrophils, fibroblasts, keratinocytes and inflammatory cells. The chemicals include “protons (H+), nerve growth factors (NGFs), cytokines (such as IL-1β, IL-6), tumor necrosis factor alpha (TNF-α), prostaglandins (PGE2), several neurotransmitters (serotonin, ATP) and peptides (bradykinin, substance P, CGRP)” (Laedermann, et al, 2015, CC By the authors) and they can activate nociceptive neurons. Inflammatory pain also increases nociceptive signaling by activating kinases that cause PTM of phosphorylation. (Laedermann, et al, 2015)
[Substance P stands for peptide - the first identified, I tend to think of it as substance Pain as it activates pain nerve cells.]
Mitogen-activated protein kinase (MAPK) is inhibited by phytonutrients in pomegranate peel extract (PPE) by the regulation of Fox03, which would decrease unwanted phosphorylation of proteins, observed in an animal-based study in which PPE reduced ototoxicity caused by amikacin (AMK). (Liu, et al, 2017) Ototoxicity, damage to Hair cells within the inner ear, is associated with certain medications like amikacin. Ototoxicity also seems to be caused by CoV, a similar sequence in the chimeric spike protein disrupts the ankyrin binding domains of TRP channels which are pressure sensing in Hair cells. (Liviero, et al, 2021)
Disruption of TRPV-1 channel function by spike protein due to the ankyrin repeat domains may affect a variety of functions in the body including hearing and cause other symptoms resembling Covid19. Liviero, et al, noted the TRPV1 symptoms and suggest trying inhibitors or down-regulators, (Liviero, et al, 2021), however TRP channels have multiple functions and just inhibiting them has not worked for other conditions.
What makes post-translational modification (PTM) of proteins more likely? Oxidative stress levels, mitochondrial dysfunction, high fructose diet, general malnutrition, lack of endocannabinoids, lack of CoQ10. That would be a different paper – or would it? See Table 5. Nutrients depleted by common psychiatric medications; and nutrients that may be deficient or imbalanced in patients with schizophrenia/schizoaffective disorder; or Alzheimer’s dementia, HD, or PD; and mitochondrial support nutrients - all four groups overlap. *and I should add a column of nutrients that may help against CoV - it would overlap too.
(Related webpage, PTM also is a causal issue in demyelination conditions: effectivecare.info/Demyelination, or more extensive document.)
*This is two subsections of my paper which is still too long, 1071 words too long currently. I did cut the doorbell part.
Coincidental aside, it doesn’t seem relevant to the paper - there has been medical research using ankyrin repeat domain proteins (DARPins) as a treatment delivery device. For cancer cell recognition to deliver a treatment in a study by Hammill, et al, 2015, the Designed ankyrin repeat proteins (DARPins) provide an antigen-targeting domain. More info: DARPins: a true alternative to antibodies. (Stumpp, Amstutz, 2007) that deserves a #coincidence in my opinion. The chimeric spike protein contains ankyrin repeat domain sequence similarities. (Liviero, et al, 2021)
“It is a small world after all.” Magic Kingdom It's A Small World (Full Ride) POV Walt Disney World HD (trauma warning - video)
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Reference List
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