Mast cell-derived BH4 is a critical mediator of postoperative pain
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Abstract
Postoperative pain affects most patients after major surgery and can transition to chronic pain. Here, we discovered that postoperative pain hypersensitivity correlated with markedly increased local levels of the metabolite BH4. Gene transcription and reporter mouse analyses after skin injury identified neutrophils, macrophages and mast cells as primary postoperative sources of GTP cyclohydrolase-1 ( Gch1 ) expression, the rate-limiting enzyme in BH4 production. While specific Gch1 deficiency in neutrophils or macrophages had no effect, mice deficient in mast cells or mast cell-specific Gch1 showed drastically decreased postoperative pain after surgery. Skin injury induced the nociceptive neuropeptide substance P, which directly triggers the release of BH4-dependent serotonin in mouse and human mast cells. Substance P receptor blockade substantially ameliorated postoperative pain. Our findings underline the unique position of mast cells at the neuro-immune interface and highlight substance P-driven mast cell BH4 production as promising therapeutic targets for the treatment of postoperative pain.
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Figure 3H
There is no Figure 3H present in the publication. Possibly a typo?
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We confirmed that surgical incision leads to a dramatic increase of the substance Pprecursors α- and β-preprotachykinin in the skin about 8 hours after incision
Since substance P precursor levels are substantially elevated in skin after surgical incision (Fig 6A), and substance P has been shown to cause degranulation, releasing a number of factors including histamine, can you postulate why you don't see elevated levels of histamine at the site of incision (Fig 3B)?
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It is possible that such mast cell-released BH4 itself contributes to painhypersensitivity by direct action on nociceptors
You elegantly show that neuronally derived BH4 contributes to the increase in BH4 levels after injury but is not involved in pain hypersensitivity. If BH4 can directly activate nociceptors, it seems like you would have noticed a decrease in pain hypersensitivity when you reduced BH4 levels. Do you think there is something chemically unique about mast cell-derived BH4 vs. neurally-derived BH4 that would allow direct activation of nociceptors?
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Altogether these experiments reveal that mast cells not only releaseBH4 and serotonin but also the necessary enzymatic machinery required for synthesis of bothmetabolites rapidly after activation.
This is a very intriguing finding-extracellular release of the enzymatic machinery necessary for BH4 and serotonin synthesis could allow signal amplification after degranulation. Is there any evidence of extracellular BH4 synthesis in other contexts from other studies? Or could these enzymes be remnants of the synthesis of serotonin within the granules?
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It is possible that such mast cell-released BH4 itself contributes to painhypersensitivity by direct action on nociceptors
You elegantly show that neuronally derived BH4 contributes to the increase in BH4 levels after injury but is not involved in pain hypersensitivity. If BH4 can directly activate nociceptors, it seems like you would have noticed a decrease in pain hypersensitivity when you reduced BH4 levels. Do you think there is something chemically unique about mast cell-derived BH4 vs. neurally-derived BH4 that would allow direct activation of nociceptors?
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Figure 3H
There is no Figure 3H present in the publication. Possibly a typo?
-
We confirmed that surgical incision leads to a dramatic increase of the substance Pprecursors α- and β-preprotachykinin in the skin about 8 hours after incision
Since substance P precursor levels are substantially elevated in skin after surgical incision (Fig 6A), and substance P has been shown to cause degranulation, releasing a number of factors including histamine, can you postulate why you don't see elevated levels of histamine at the site of incision (Fig 3B)?
-
Altogether these experiments reveal that mast cells not only releaseBH4 and serotonin but also the necessary enzymatic machinery required for synthesis of bothmetabolites rapidly after activation.
This is a very intriguing finding-extracellular release of the enzymatic machinery necessary for BH4 and serotonin synthesis could allow signal amplification after degranulation. Is there any evidence of extracellular BH4 synthesis in other contexts from other studies? Or could these enzymes be remnants of the synthesis of serotonin within the granules?
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