Accurate Education – Palmitoylethanolamide (PEA)

The history of PEA as a natural food ingredient with medicinal properties was first identified in 1943 as part of an epidemiological study focused on childhood rheumatic fever,  which was noted to occur more frequently in those children who ate fewer eggs. Subsequently investigators noted that the occurrence of rheumatic fever was reduced in children fed egg yolk powder. Subsequently PEA was first identified in the 1950s as being an active anti-inflammatory agent in chicken egg yolk.

Conditions with Evidence of Benefit with PEA

1. Arthritis – osteoarthritis & rheumatoid athritis
2. Fibromyalgia
3. Peripheral neuropathies – diabetic neuropathy & chemotherapy-induced peripheral neuropathy
4. Carpal tunnel syndrome
5. Opioid Tolerance and Hyperalgesia
6. Low back pain – herniated disc disease, failed back surgery syndrome, other
   
7. Sciatic pain
8. Dental pain
9. Neuropathic pain – related to stroke & multiple sclerosis
10. Inflammatory Bowel Disease
11. Chronic pelvic pain
12. Shingles pain (postherpetic neuralgia)
13. Vaginal pain (vulvadynia)
    
14. Post-operative dental surgery pain
15. Traumatic Brain Injury/Chronic Traumatic Encephalopathy

Particular cells of the immune system intimately associated with or located within the nervous system, i.e., “non-neuronal cells”, are major contributors to the development and maintenance of chronic pain. In particular, mast cells (within the nervous system and in the periphery) and microglia (at spinal and supraspinal (brain) level) interact with neurons under physiological and pathological conditions.

PEA acts as an Autacoid Local Injury Antagonist (ALIA), through reducing mast cell de-granulation which releases multiple compounds that trigger inflammation. It has also been found that PEA is synthesized by mast cells and microglia and is able to keep these cells reactivity within normal physiological boundaries, thereby controlling neuroinflammation and chronic pain.

It has also been shown that PEA not only acts through non-neuronal cells as described above, but may also directly influence neurons. PEA has been shown to (i) exert protective effects on cortical and cerebellar neurons, (ii) control spontaneous GABAergic synaptic activity in striatal neurons, (iii) dose-dependently increase intracellular calcium concentration in sensory neurons thereby desensitizing pain receptors; (iv) modulate the activity of dorsal root ganglion neurons.

GPR55 forms receptor heteromer with either CB1 or CB2 receptors raising the possibility that PEA might modulate CB1- and/or CB2-mediated intracellular signaling by targeting the GPR55 protomer in these putative GPR55/CB1 or GPR55/CB2 heterodimers.

PPARs are  involved in regulating biological processes such as pain processing, lipid metabolism, energy balance, fat production, inflammation and cell growth and differentiation. When activated PPARs in immune and brain cells regulate gene expression leading to transcription and production of proteins involved in pain processing, fatty acid oxidation and metabolism. PEA produces analgesic effects via PPARα directly and recent studies have demonstrated that PEA increases the levels of CB2 receptor mRNA and protein as a result of PPAR-α activation and indirect activation of CB1 receptors as particularly noted in osteoarthritis pain.

Mast Cells

Mast cells are immune cells mostly located within tissues at the boundary of the external environment, in close proximity to blood vessels and nerve endings and found also within the endoneurial compartment (lining) of peripheral nerves.

Mast cells can modify sensory transmission via a wide spectrum of mediators, including biogenic amines such as histamine and serotonin, cytokines (interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) in particular), enzymes, lipid metabolites, ATP, neuropeptides, nerve growth factor (NGF), and heparin—most of which can interact with sensory nerve terminals. Sensory neurons, in turn, by releasing neuropeptides may provoke mast cell activation/ degranulation.

Mast cell-nerve terminal activity results in nociceptor sensitization, reduced pain threshold at the site of inflammation and, ultimately, dysfunctional pain signaling and hyperalgesia and when it persists, increased responsiveness of nociceptors can also sensitize spinal cord neurons, leading to central sensitization.

Mast Cells and Pain Associated with Cold Weather and Weather Change

Mast cells are perhaps the body’s most sensitive sensors for detecting changes in the external environment. They are located along blood vessels and nerves, particularly near the skin’s surface where they have been shown to be responsive to changes in environmental temperature and baroumetric pressure. It has been proposed (by Dr. Ehlenberger) that given their role in nerve pain and their ability to detect and respond to environmental change, mast cells may play a key role in why patients with chronic pain, especially nerve pain, arthritis and fibromyalgia, experience worse pain in cold weather and with changes in weather associated with changes in barometric pressure as occur prior to weather changes. The stabilizing effect PEA has on mast cells suggests that PEA may be an effective treatment for reducing pain sensitivity to cold weather and weather change.

Glial Cells

Glia cells mediate pain processing at the spinal level. Sensitization of central somatosensory neurons is  responsible for the development of chronic neuropathic pain. Microglia, macrophages found in the brain, interact with neurons at the site of injury or disease and can be activated through exposure to a number of  molecules, including pro-inflammatory signals released from mast cells. A bidirectional cross talk between brain mast cells and microglia has been theorized, contributing to chronic pain states by releasing pro-inflammatory cytokines, chemokines, and proteases.

Astrocytes, the most abundant glial cell type involved in neuroinflammation, also play a major role in pain processing, contributing to neuropathic pain. When activated, astrocytes release of IL-1b, IL-6, TNF-a and prostaglandin E2. Chronic astrocytic activation in nerve injury results in down-regulation of glutamate transporters, ultimately resulting in decreased glutamate uptake and increased excitatory transmission and facilitation of chronic pain.

PEA, Mast Cells and Glial Cells

These chronic neuroinflammatory processes that sustain neuropathic pain are opposed by the production of lipid mediators that are able to switch off inflammation. Assuming that chronic inflammation may lower the levels or actions of these molecules, it is believed that administration of such lipid mediators might provide an reverse or suppress neuroinflammation. N-acylethanolamines (NAEs) are a class of naturally occurring lipid mediators composed of a fatty acid and ethanolamine—the so-called fatty acid ethanolamines (FAEs). The principal FAEs include the endocannabinoid N-arachidonoylethanolamine (anandamide), and its congeners N-stearoylethanolamine, N-oleoylethanolamine and N-palmitoylethanolamine (PEA or palmitoylethanolamide).

PEA, produced by microglia and mast cells, down-modulates mast cell activation and controls microglial cell activity. By controlling these cells, PEA acts is disease-modifying rather than symptom-modifying, since it acts on the ‘‘roots of the problem’’, i.e., on the cells involved in the generation and maintenance of pain. In support of this theory, PEA levels have been shown to be altered in brain and spinal cord areas involved in pain when pain is induced.

Other Mechanisms of Action

PEA activates peroxisome proliferator activated receptors (PPAR) in cell nuclei of both dorsal root ganglion sensory neurons and glial cells. This receptor is a regulator of gene networks which control pain and inflammation. Stimulation of PPAR-a modulates both the perception and transmission of peripheral pain signaling and spinal amplifying pain mechanisms—thereby exerting its activity in different types and phases of pain. PEA also potentiates the endocannabinoid, anandamide’s, actions at cannabinoid receptors (CB2 receptors) on cell membranes, while itself having no appreciable affinity for either CB1 or CB2 receptors, making it an indirect CB2 agonist.

PEA thus possesses two pain-relieving therapeutic effects, a reduction of neuroinflammation and a reduction in pain signaling and transmission.