Serotonin (5-HT) promotes (chronic) pain and, likely, depression as well
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Evil serotonin rears its ugly head again. This time, the findings of the study below are that serotonin may be the primary driver of post-surgical pain, which often becomes chronic and may lead to depression, opioid/alcohol addiction, anti-social behavior, etc. So much for serotonin being the “cure” of depression. Now, while the study below looked only at post-surgical pain, in my opinion the findings are not specific to that situation only. Namely, the inflammatory state (driven by mast cell activation), which most patients find themselves in after surgery is characterized by inflammatory mediators found systemically and not just in the organ/tissue operated on. This means that serotonin may be responsible for many/most cases of “idiopathic” chronic pain seen in people without physical trauma or surgery. Interestingly, systemic inflammation and chronic pain are a common observation in depression, which may explain why anti-inflammatory drugs (many of which are also analgesics) are often therapeutic in depression. Furthermore, many studies have observed a very strong correlation between levels of inflammation and chronic pain and severity of depressive symptoms. As such, one can plausibly conclude that the administration of SSRI drugs directly promotes at the very least chronic inflammation and pain, and likely depression as well. Unfortunately, I suspect it will be decades before we see such a direct conclusion in a study like the one below, published in a highly reputable journal.
The study used genetic deletion of the enzyme tryptophan hydroxylase (TPH), which produced serotonin, in order to block the post-surgical pain. This method is obviously not practical to implement in humans, so instead one could probably achieve the same effects using serotonin antagonists such as cyproheptadine and metergoline, or the (even better) the over-the-counter anti-acid drug famotidine, which was found to be a powerful anti-serotonin agent capable of stopping already established serotonin syndrome (which is often lethal).
https://www.science.org/doi/10.1126/sciimmunol.adh0545
“…Inflammation caused by surgical tissue injury can evolve into chronic pain. Starkl et al. used a mouse model of surgical tissue injury to decipher a role for mast cell–derived metabolites in postoperative pain. Tetrahydrobiopterin (BH4) has been previously detected in injured nerves and correlates with pain intensity and is required for serotonin production by tryptophan hydroxylase (Tph1). Nerve-proximal mast cells were identified as a source of GTP cyclohydrolase 1 (Gch1), a rate-limiting enzyme for BH4 synthesis. Deletion of Gch1 or Tph1 from mast cells or mast cell depletion reduced tissue injury pain. The nociceptive neuropeptide substance P was detected at tissue injury sites and triggered BH4-dependent serotonin release from mast cells, thus defining how neuropeptides can act on mast cells and propagate pain responses.”
“…Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.”
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do you think famotidine is superior to cyproheptadine to keep in the medicine cabinet?