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.” []

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:[]
  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:[] (*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). []
  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. [] [] 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.[] *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:[]
  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.] Full text available: []
  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).” []
  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: []

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./

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