Tag Archives: substance P

An article on Morgellons; a link, and a comment I added re keratinocytes

Morgellons, chapter from a book, skeptic busting or quack busting, but open-minded regarding the sufferers having a real itch problem rather than a delusional psychiatric disorder as the mainstream medical world is treating the condition. Sufferers have lost jobs due to a condition that has no physical diagnosis:[https://medium.com/matter/the-itch-nobody-can-scratch-4d980e3ac519#.tcwvu9neq]

It is horrible to have physical symptoms that are dismissed as “all in your head,” — that is no help if there is pain in your skin or under your skin.

I added a comment, slightly edited here:

Maybe they have overactive keratinocytes that produce Substance P and causes itch and neuropathic pain. Magnesium deficiency can lead to increased production of Substance P.

“Keratinocytes are able to detect itch-associated signals by expression of protease-activated receptor-2,[11] opioid,[12] cannabinoid[13] and histamine H4 receptors.[14] By responding to these signals, keratinocytes can modulate itch in many ways. For example, keratinocytes can release neurotrophins including NGF[15,16] and neurotrophin-4[17] (Fig. 1), lipid mediators[18] or endothelin-1,[19] which can either directly activate itch fibres in the skin or activate mast cells to release pruritogenic mediators. In addition, neuropeptides including substance P have been shown to significantly increase the release and production of NGF of human cultured keratinocytes, indicating a neuroimmune interaction mechanism between sensory nerves and keratinocytes[20] (Fig. 1). Interestingly, keratinocytes can also inhibit itch through the release of endocannabinoids, which bind directly to inhibitory receptors on sensory nerves.”

— so maybe the Morgellons sufferers have a defect or insufficiency in endocannabinoids. Epsom Salt baths for magnesium in case gastrointestinal absorption of magnesium is a problem might help, and supplements with phospholipids like phosphatidylcholine or phosphatidylserine might help if endocannabinoid deficiency is a problem — or chocolate, rosemary and nutmeg are food sources.

Excerpt from: “Pathophysiology of Itch and New Treatments,” Ulrike Raap; Sonja Ständer; Martin Metz, Curr Opin Allergy Clin Immunol. 2011;11(5):420–427. [http://www.medscape.com/viewarticle/749608_2]

/Disclaimer: Opinions are my own and  the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./

Substance P, neuropathic pain, migraines, and the cannabinoid system

Our bodies don’t have specific receptors just for sensing “pain.” Pain is a sign that something is wrong in the body and is sensed in a variety of ways. In medical terminology there are two main types of “pain.” Nociceptive pain is associated with physical damage to the body or by sensations of pressure or heat or extreme cold. It might be due to pressure from a cancer tumor. Nociceptive pain might be described as “sharp, aching or throbbing.” Neuropathic pain is caused by physical damage or pressure on nerves. It might also be due to a cancer tumor but one that is pressing on a nerve. Nerve damage can also be due to some nutrient deficiencies such as vitamin B12, [B12}, or other “Nutritional imbalance, alcoholism, toxins, infections or auto-immunity.” Neuropathic pain often is described as “a burning or heavy sensation, or numbness along the path of the affected nerve.” [http://www.medtronicneuro.com.au/chronic_pain_commontypes.html]

Some types of pain such as migraine headaches may involve both nociceptive pain due to the pressure of inflammation or dilation of blood vessels an neuropathic pain from pressure on nerves by dilated or inflamed blood vessels.

  1. G. La Rana, et al., AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: Role for cannabinoid receptors, Neuropharmacology, Vol. 54 Issue 3, March 2008, Pages 521–529 Abstract opening: “Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. ” Read more, Abstract available:[http://www.sciencedirect.com/science/article/pii/S0028390807003504]
  2. Paul L. Durham, Ph.D., Calcitonin Gene-Related Peptide (CGRP) and Migraine, Headache. 2006 Jun; 46(Suppl 1): S3–S8. Excerpt: “Activation of trigeminal sensory nerve fibers causes a pain response to be conveyed to the brainstem (and from there to higher brain centers) and evokes release of vasoactive peptides such as substance P and CGRP from trigeminal fibers. These peptides exacerbate vasodilation and cause neurogenic inflammation characterized by vasodilation, leakage of blood vessels, and degranulation of mast cells.4 ”  Levels of CGRP increase in people who suffer from migraines and a type of prescription medication, called sumatriptan, which has been found helpful to stop migraine pain, has also been found to inhibit the release of CGRP in migraine patients. The medication may be inhibiting the release of CGRP by increasing intracellular levels of calcium (*which might then be causing an increased release of endogenous cannabinoids from membrane storage.) “The cytokine TNF-α was studied in view of previous observations that it is among the most consistently elevated cytokine in migraine and that it, like nerve growth factor in the experiments described above, activates MAPK pathways in various cell types including neurons.19 The results of the investigations reveal that TNF-α-1 receptors were present on most CGRP-containing rat trigeminal ganglia neurons. In addition, CGRP release from cultured trigeminal neurons was increased after treatment with TNF-α or ceramide, an intracellular signaling intermediate from the TNF-α-1 receptor.“Read more, Full text available:[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134175/] (*TNF = Tumor Necrosis Factor. Increased levels of ceramide are found in Alzheimer’s and it is involved in the cannabinoid membrane system also. Ref’s: Surprising finding provides more support for Alzheimer’s being an autoimmune disease  ,  *Activating cannabinoid receptors type 1 –> production, which mediates cannabinoid induced apoptosis – p67 )
  3. Calcitonin is a hormone released by the thyroid that promotes lower blood calcium levels by reducing bone resorption (bone resorption: breakdown of the bone and release of minerals). [http://medical-dictionary.thefreedictionary.com/calcitonin]
  4. Calcitonin Gene-Related Peptide 1 and 2 cause dilation of blood vessels in the heart and brain and throughout the body. Its prevalence in the Central Nervous System (CNS) also suggests that it may also have a neurotransmitter or neuromodulator role. [http://www.uniprot.org/uniprot/P06881] [http://www.uniprot.org/uniprot/P10092] CGRP is produced by nerve cells in the brain and throughout the body. The protein has a role in sensations of pain. It is a member of the calcitonin family of proteins and exerts its effects at receptors that are formed from two other types of receptors including the “calcitonin receptor-like receptor (CALCRL) and a receptor activity-modifying protein (RAMP1).[7] ” ”  The alpha form of the protein may help reduce pain while the beta form is associated with migraine, temporomandibular joint (TMJ) pain, psoriasis (an eczema-like condition believed to be autoimmune in nature), and irritable bowel syndrome (IBS). The beta form is largely produced in keratinocytes found in the epidermis layer of skin. The alpha form is the type produced more within sensory nerves.[https://en.wikipedia.org/wiki/Calcitonin_gene-related_peptide] *Note to self — ouch. I have had severe migraines, TMJ, symptoms like IBS, and severe eczema throughout much of my life. My keratinocytes may be the common element.
  5. Quanzhi Hou, et al., Keratinocyte expression of calcitonin gene-related peptide β: Implications for neuropathic and inflammatory pain mechanisms, Pain, Vol 152, Issue 9, September 2011, Pages 2036–2051, Keratinocytes also express the two types of receptors that form the CGRP receptor. Read more, Abstract available:[http://www.sciencedirect.com/science/article/pii/S0304395911003137]
  6. Xiaoyou Shi, et al., Neuropeptides Contribute to Peripheral Nociceptive Sensitization by Regulating Interleukin-1 Beta Production in Keratinocytes, Anesth Analg, 2011, July 113(1) 175-183, This article includes a discussion of Substance P and CGRP levels in a type of chronic peripheral pain condition and whether Substance P and CGRP might cause an increased production of IL-1beta. The discussion mentions that an abnormal response to capsaicin is observed in patients with the chronic peripheral pain condition called “complex regional pain syndrome (CRPS).” [Capsaicin is the active phytochemical found in hot peppers which can also be a trigger for symptoms of Irritable Bowel Syndrome. https://en.wikipedia.org/wiki/Capsaicin] Full text available: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123433/]
  7. Capsaicin is the active phytochemical found in hot peppers which can also be a trigger for symptoms of Irritable Bowel Syndrome. Except probably not in birds: “The seeds of Capsicum plants are dispersed predominantly by birds: in birds, the TRPV1 channel does not respond to capsaicin or related chemicals (avian vs mammalian TRPV1 show functional diversity and selective sensitivity).” [https://en.wikipedia.org/wiki/Capsaicin]
  8. I love search engines and the large volume of knowledge available online. Somewhat related posts on this site:  1) And what do osmomechanical stress, changes of temperature, chili powder, curry powder, ginger, Benicar, hormone D, steroids, and cannabinoids have in common? (Answer – TRPV1 channels and Irritable Bowel Syndrome.) 2) Links about magnesium deficiency and Substance P, a neuropeptide associated with inflammation, .

Time for an Epsom bath perhaps.

Epsom salt baths can be a well absorbed source of magnesium because skin absorption will bypass a problem of poor intestinal absorption of magnesium. Calcium tends to be preferentially absorbed by the intestines, especially when there is an imbalance in vitamin and hormone D levels and poor intestinal absorption of magnesium over time can easily lead to symptoms of magnesium deficiency. Symptoms of magnesium deficiency are usually labeled something else by the medical profession because the problem is not obvious on lab tests until it is quite severe because the body takes more magnesium from the bones as needed up until the point where osteoporosis is severe  enough to cause a shortage of stored magnesium.

Soaking in a bathtub for twenty minutes that has one cup of Epsom salt to a half full bathtub, and one teaspoon of a cooking vinegar such as apple cider vinegar to balance the alkalinity of the Epsom salt, can be a cure for a bad mood as well as various achy muscle cramps if magnesium deficiency is an underlying problem. Negative symptoms can occur if you stay in the bath too long. Excess magnesium absorption can cause loose watery stools for an entire day, not just once. Falling asleep in the bath can also lead to more life threatening symptoms of a weak, and fluttery heart rate, or even lead to coma and/or death — so twenty minutes to forty minutes is probably safe for a deficient person while someone who isn’t deficient might notice a weak slowing heart rate sooner than the twenty minute average that a person deficient in magnesium might find only as calming and soothing to  their mood and muscles. A person who was deficient but who then started taking the baths regularly might start noticing the weak heart rate sooner — get out of the tub then, even if its not been twenty minutes — shower and rinse time. Research on the therapeutic use of Epsom salt baths recommended one cup Epsom salt to the half full/full bath and use up to three to four times per week, but not daily.

I can’t find the actual research study among the following posts of mine (see below) but Dr. Oz has an article on the baths also and recommends the twenty minutes a few times a week also: [http://blog.doctoroz.com/oz-experts/restoring-magnesium-levels-with-epsom-salt-baths]

Previous posts on magnesium deficiency and Epsom salt baths:

1) Autistic kids wash up happier in an Epsom salt bath, .

2) Hypomagnesemia symptoms and causes list, .

3) Magnesium deficiency can cause irritability, anxiety, and chronic degeneration, .

4) Note to self: Epsom salt bath first, keyboard second; Irritability, Schizophrenia, T. gondii, and hormone D, .

An update on schizophrenia, unrelated to Substance P, migraines, or Epsom Salt baths:

5) The voices that people with schizophrenia are hearing are probably their own inner thoughts, .

/Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./

Links about magnesium deficiency and Substance P, a neuropeptide associated with inflammation

Magnesium is Essential for Preventing Substance P Overload , May 24, 2011, by Byron J. Richards, Board Certified Clinical Nutritionist , “Substance P is a neuropeptide that is typically ”over-heated” in situations of anxiety, depression, digestive bloating, insomnia, fibromyalgia, PTSD, and cardiovascular deterioration. New research shows that one of the first signs of magnesium deficiency1 is that it enables the over-production of substance P.” Read More:  [http://www.wellnessresources.com/health/articles/magnesium_is_essential_for_preventing_substance_p_overload/]

Raw shelled pumpkin seeds are a good source of magnesium, zinc, B vitamins and essential fatty acids. A few prenatal clients that I have worked with in the past, who were high risk due to a history of high blood pressure or pre-eclampsia during their first pregnancy, did report that the raw shelled pumpkin seeds that I had recommended they try adding to their diet during their second pregnancy did seem helpful for preventing high blood pressure or pre-eclampsia from reoccurring.  So it is also possible that raw unsalted pumpkin seeds may be a beneficial food for use during the perinatal stage for women who hope to prevent autism from developing in their infant during conception or the early weeks of pregnancy. [http://transcendingsquare.com/2014/07/24/magnesium-might-help-protect-against-beta-amyloid-placques/]

/Disclosure: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./

Additional notes to think more about later:

  1. Gehan A Mostafa; Laila Y AL-Ayadhi, The Possible Link Between the Elevated Serum Levels of Neurokinin A and Anti-ribosomal P Protein Antibodies in Children with Autism, J Neuroinflammation. 2011;8(180) Excerpt from the background section: “Neurogenic inflammation is orchestrated by a large number of neuropeptides. Tachykinins (substance P, neurokinin A and neurokinin B) are pro-inflammatory neuropeptides that may play an important role in some autoimmune neuroinflammatory diseases. Autoimmunity may have a role in the pathogenesis of autism in some patients.” And an excerpt from the discussion section: “In our series, increased serum levels of anti-ribosomal P protein antibodies were found in 44.3% of autistic patients. This study was the first to investigate serum levels of anti-ribosomal P protein antibodies in autistic children.” [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261830/]
  2. Julio Hernandez, et. al., Substance P Is Responsible for Physiological Alterations Such as Increased Chloride Ion Secretion and Glucose Malabsorption in CryptosporidiosisInfect. Immun. March 2007 vol. 75 no. 3 1137-1143
    [http://iai.asm.org/content/75/3/1137.full] *Cryptosporidiosis is a parasitic infection that can be more of a risk for AIDS patients than for average people — reason unknown — The reason speculatively might be that there is a magnesium deficiency or an elevated calcium level resulting from elevated hormone D levels underlying the increased risk for crypotosporidiosis in AIDS patients.
  3. Sylke Müller1 and Barbara Kappes, Vitamin and co-factor biosynthesis pathways in Plasmodium and other apicomplexan parasitesTrends Parasitol. 2007 Mar; 23(3): 112–121.
    This article is primarily about a few B vitamins and protozoan parasites but one section addresses vitamin D, Excerpt: “One way in which vitamin D3 might affect Plasmodium is through its involvement in phospholipid metabolism and signalling pathways 60. Vitamin D3 and analogues have pronounced inhibitory effects on P. falciparum erythrocytic late stage development possibly because the phospholipid biosynthesis pathways of the parasite is affected by these compounds 61. Inhibition of phospholipid biosynthesis by other classes of inhibitors (for instance choline analogues) has been followed up extensively 62, 63 and it is likely that these inhibitors will be developed as new drugs against malaria in the near future 64. Thus the activity of vitamin D3 analogues merits further attention.” [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330093/]
  4. 60. Boyan BD, et al. 1,25-(OH)2D3 modulates growth plate chondrocytes via membrane receptor-mediated protein kinase C by a mechanism that involves changes in phospholipid metabolism and the action of arachidonic acid and PGE2. Steroids. 1999;64:129–136. [PubMed] *Roughly this title could be translated into: Hormone D affects growth plate cartilage cells by affecting the endogenous cannabinoid system, — arachidonic acid and PGE2 can be formed from cannabinoids that are released from storage within cell membranes. Elevated levels of calcium intracellularly can be a trigger signalling the release of endogenous cannbinoids from the membranes.
  5. 7. Regulation of growth plate chondrocytes and bone cells,                                        Excerpt: “In recent years it has been demonstrated that a large number of growth factors and cytokines regulate the proliferation and differentiation of bone and cartilage cells in vitro and in vivo (Table 2). This subject has been extensively reviewed (Goldring & Goldring, 1990; Canalis, McCarthy & Centrella, 1988a; Price & Russell, 1992; Martin, 1989). There is also increasing evidence that abnormal production of cytokines in diseases such as rheumatoid arthritis, osteoarthritis and osteoporosis may result in inappropriate responses by bone and cartilage cells. Those cytokines and growth factors considered to be of particular importance during bone development and growth include the IGFs, TGF a and b, bone morphogenetic proteins (BMPs), FGF, PDGF and epidermal growth factor (EGF). Many of the cell types present in the microenvironment of growing bone contribute to the local synthesis of cytokines and growth factors including the resident endothelial cells, marrow stromal cells, osteoblasts, periosteal cells and chondrocytes. The haemopoetic cells present in bone marrow include circulating monocytes, macrophages and T cells; these are another potential source of cytokines. In fact, several lines of evidence point to there being a close relationship between bone cells and cells of the immune system (Skjodt & Russell, 1993).”

    7.12. Parathyroid hormone related peptide (PTHrP)

    “PTHrP is a peptide closely related to PTH that is produced by normal tissues, with similar effects to PTH on bone. It has been established as having an important role in regulating the hypercalcaemia that is associated with some malignancies (Webb et al., 1988). PTHrP has also been identified as a fetal hormone which may regulate placental calcium (Ca2+) flux (Orloff, 1989). This peptide may also have an important role in skeletal development, having been localised in embryonic bone, and a recent study has shown that mice with a defective PTHrP gene have multiple skeletal abnormalities (Karaplis et al., 1992).” [http://archive.unu.edu/unupress/food2/UID06E/UID06E0V.HTM]

  6. Arnold J. Felsenfeld, et. al., Dynamics of Parathyroid Hormone Secretion in Health and Secondary HyperparathyroidismCJASN November 2007 vol. 2no. 6 1283-1305 [http://cjasn.asnjournals.org/content/2/6/1283.full]

  7. S. C. Kukreja, et. al., Antibodies to parathyroid hormone-related protein lower serum calcium in athymic mouse models of malignancy-associated hypercalcemia due to human tumors. J Clin Invest. 1988 Nov; 82(5): 1798–1802 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC442751/] Abstract: “A parathyroid hormone-related protein (PTHrP) has recently been isolated from tumors associated with hypercalcemia. In the present study, we tested the effects of neutralizing antisera to the PTHrP on serum calcium and urine cAMP in two animal models of malignancy-associated hypercalcemia. The animal models consisted of (a) a human squamous cell lung cancer and (b) a human laryngeal cancer, both serially carried in athymic mice. The antisera specifically reduced the elevated serum calcium and urinary cAMP levels in the tumor-bearing animals. We conclude that PTHrP plays a major role in the pathogenesis of malignancy-associated hypercalcemia.”

  8. Moniz C., et. al., Parathyroid hormone-related peptide in normal human fetal development., J Mol Endocrinol. 1990 Dec;5(3):259-66. [http://www.ncbi.nlm.nih.gov/pubmed/2288637Abstract:

    “Parathyroid hormone-related peptide (PTHrP) has been detected in fetal serum and amniotic fluid. Using a combination of immunocytochemistry and molecular biology we have detected the peptide and its mRNA in a variety of fetal tissues throughout gestation. Tissue-specific mRNA isoforms were observed, the pattern of hybridization of which changed throughout gestation. In addition, the intensity and pattern of immunocytochemical localization of the peptide was found to vary over the time-period studied (8-30 weeks). PTHrP is expressed by a variety of tumours associated with the syndrome of humoral hypercalcaemia of malignancy and probably accounts for the hypercalcaemia by virtue of its limited amino acid homology with parathyroid hormone. These data demonstrate for the first time that PTHrP, a tumour-related peptide, is expressed during normal human fetal development, and suggest the possibility that it may function to regulate fetal calcium balance and growth in utero.”


  9. “Parathyroid hormone-related peptide (PTHrP) can be elevated in pregnant and lactating women and in newborn infants. Nonmalignant conditions that have been described in association with elevated plasma PTHrP levels include systemic lupus erythematosus, HIV-associated lymphadenopathy, lymphedema of chest or pleural cavities, and with benign tumors of the ovary, kidney and the neuroendocrine system.” [http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/81774]
  10. Shane T. Mortimer, David A. Hanley, William K. Stell, Immunohistochemical identification of calcitonin gene-related peptide and substance P in nerves of the bovine parathyroid gland., Cell and Tissue Research
    , Volume 261, Issue 2, pp 339-345, [http://link.springer.com/article/10.1007/BF00318675Summary:

    “Although peptide neurotransmitters have been shown to modulate hormone secretion in many glands, there are very few studies of neurotransmitters in the parathyroid gland. Bovine parathyroid glands were collected at a local abattoir, fixed with paraformaldehyde, sectioned using a cryostat, and stained by indirect immunohistochemistry for calcitonin gene-related peptide and substance P. We were able to positively identify both neuropeptides. Nerve fibres containing calcitonin gene-related peptide and substance P were identified in contact with the tunica media of arteries and arterioles and dispersed throughout the stroma of the gland. While many of the fibres encircled parenchymal lobules, no intimate contact with the peripheral chief cells was observed. All immunoreactive fibres were found to contain both neuropeptides. Since calcitonin gene-related peptide and substance P are vasodilators, they may increase blood flow within the gland. In addition, the neuropeptides may diffuse from perilobular nerve fibres into the parenchyma, thereby modulating secretion of parathyroid hormone.”

  11. And for the swish and score — calcitonin gene-related peptide is associated with migraine attacks — hmmmmm — health is a miracle when it works. [https://migraine.com/blog/what-is-calcitonin-gene-related-peptide-cgrp/]