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Metabolism, Mast cells and palmitoylethanolamide

 Metabolism and pain

Many new inroads are being explored in the treatement of chronic pain, and influencing metabolism of key players in the pain field is emerging as a new opourtunity.[1] FAAH, the enzyme which degrades palmitoylethanolamide and anadamide for instance, is currently targetd by a peripherally restricted inhibitor (URB937). URB937 suppressed FAAH activity and increased anandamide levels outside the CNS leading to treatment relevant effects. [2] And, as inhibitors of fatty acid amide hydrolase (FAAH), are effective in a number of animal models of pain other new targets are also described, such as isoflavones, with respect to their abilities to inhibit FAAH. Biochanin A for instance inhibited the spinal phosphorylation of extracellular signal-regulated kinase which play a role in pain behavior. [3]

Another exemple of a target influencing metabolic routes is 5-Lipoxygenase (LOX), is an important arachidonic acid-metabolizing enzyme producing leukotrienes and other proinflammatory lipid mediators with potent functions in inflammatory diseases. 4-(3-(4-(1-Methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (PF-4191834) is such a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. [4]

N-palmitoyl-ethanolamine (PEA) has emerged recently as an important local pro-homeostatic mediator which can be also administered exogenously as the active principle of current anti-inflammatory and analgesic preparations. Its use is based on our recent understanding of the mechanisms regulating both the tissue levels of PEA under physiological and pathological conditions. To influence its metobolism synthetic tools that selectively retard its catabolism are under development, such as the inhibitors of the recently cloned N-acylethanolamine-hydrolyzing acid amidase. [5]

Here we briefly discuss the relation between mast cells, metabolic routes related to pain and painstates such as migraine and CRPS type 1.

Migraine, trigeminal neuragia, mast cells and metabolism

Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors. These meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells.

Degranulation of dural mast cells induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by a clear disturbance in cellular metabolism, as it is followed by an increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), which is an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction also leads to other metabolic disturbances, such as downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression.

Based on these data mast cell degranulation could even be regarded as linked to the pathogensis of migraine and trigeminal neuralgia, as prolonged activation of the trigeminal pain pathway is believed to underlie intracranial headaches such as that of migraine and painstates such as trigeminal neuralgia. [6]

The Complex Regional Pain Syndrome type 1 and mast cells

The Complex Regional Pain Syndrome type 1 (CRPS1) is a complication of surgery or trauma and although the pathogenesis remains debatable, metabolic changes in local tissue lead related to mast cell activity lead to activity of proinflammatory cytokines IL-6 and TNFalpha which translate into inflammatory processes.

Twenty patients fulfilling the criteria for CRPS1 in one extremity were studied. Blisters were made with a suction method in order to determine cytokines and mast cell derived tryptase in the involved and uninvolved extremity.

In the blister fluid a significant difference was found between the involved and uninvolved extremity in IL-6, TNFalpha , and tryptase. There was a significant correlation (0.455) between the intensity of pain and tryptase levels in the involved extremity, leading to the conclusion that mast cells are involved in inflammatory reactions during the CRPS1. [7]

Mast cells influences metabolism microglia leading to inflammation cascades

The brain-derived neurotrophic factor (BDNF) plays a critical role in pain hypersensitivity and functions as a ligand of P2X4 receptors (P2X4R) in the microglia.

Mast cell activation markedly promoted the expression of P2X4R and BDNF in microglial cells, which significantly enhanced the release of BDNF from microglial cells upon exposure to adenosine triphosphate. Mast cell-derived tryptase activation leads to promoting the expression of P2X4R in microglial cells.[8]

In the picture from the article Beyond Neurons: Evidence That Immune and Glial Cells Contribute to Pathological Pain States from Watkins and Maier we see the various inflammatory compounds changing metabolism of gia to secrete further inflammatory cytokines and mediators such as NO and ATP, as well as ROS and other autocoids such as prostaglandines.[9] Thus neuropathic pain can be seen as a metabolic disturbance and metabolism modulating compounds such as palmitoylethanolamine can be used to correct this disturbed metabolic state.

Metabolism of Mast cells after activation

Mast cells are found in all human tissues.Their cytoplasm is loaded with granules containing many key mediators of inflammation.Their surface is coated with a great variety of receptors which can trigger exocytosis of the granules. Via this proces mast cells influences local tissue metabolism and this leads to inflammation. Activated mast cells release a whole cascade of potent mediators. Some of these immediately as they discharge their granules, some others later as mast cell metabolism changes more and these cells start synthesizing these second wind mediators via new gene transcription.

These mediators recruite all the types of white blood cell to the sitemonocytes that become macrophages when they leave the blood and enter the tissue. Many of these recruited cells in their turn start changing their metabolsim and synthesisze and form their own mediators of inflammation.

Mast cells themselves turn on their metabolism during the inflammation processes and the many alike states in neuropathic pain and large amounts of TNF-α are quickly released. All the other cells involved in inflammation, as well as gliacells have receptors for TNF-α, and are activated by it to (mal) dapt their metabolism and start synthesize more mediators of their own. In such a way an maladepted augmentation of response drives metabolsim of all these cells into the direction of inflammation and neuropathic pain states.

Tryptase is also abundantly synthesized and released by mast cells. It is a serine protease and cleaves peptide bonds on the C-terminal side of arginines and lysines, activating C3 of the complement system and contributing to inflammatory cascades.

Activated mast cell metabolism also changes into producing masive histamine and releases this potent inflammatory mediator.

Mast cell metabolism changes leads to enhanced synthesis of prostaglandins such as eicosanoid and other lipids which can cause vasodilation, fever, and neuropathic pain.

Mast cells, fibroblasts, endothelial cells, Schwann cells, resident macrophages, and resident dendritic cells all play together and the importance of proinflammatory cytokines (TNF, IL-1, IL-6) in the pathological pain is the most consistent finding across all animal and human neuropathic pain models. NO, ROS, and complement have also been implicated in this pathogenesis.

Compounds able to modulate mast cell metabolism such as palmitoylethanolamide therefore are promising new kids on the block for treating neuropathic painstates.

Chronic Pain Coalition Chronic Pain Coalition

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