DuggaDugga
Member
- Joined
- Jun 7, 2017
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- 204
Just starting to research this topic, so I figured I'd shared what I've been reading to solicit feedback from you all.
Virtually without question, but with some potential exception to receptor-specificity, serotonin has been implicated in the initiation of hibernation in animals:
Brain serotonin metabolism in hibernation. - PubMed - NCBI
Induction of unseasonable hibernation and involvement of serotonin in entrance into and maintenance of its hibernation of chipmunks T. asiaticus. - PubMed - NCBI
Does serotonin play a role in entrance into hibernation? - PubMed - NCBI
Same with melatonin, which seems to regular glucose homeostasis (insulin resistance), fat accumulation in preparation and endurance of hibernation, along with regulating sensitivity to light:
Plasma melatonin concentrations in hibernating marmots: absence of a plasma melatonin rhythm. - PubMed - NCBI
Melatonin modulates glucose homeostasis during winter dormancy in a vespertilionid bat, Scotophilus heathi. - PubMed - NCBI
This got me to thinking about the role of serotonin in mediating torpor/"hibernation" in animals, along with histamine and melatonin, modified sensitivity to light, sound, pain, and brain inflammation. It seems logical that increased serotonin may play a role in the reclusive, irritability that is experienced by many individuals chronically, especially those suffering from migraines (hyper-sensitivity of 5HT3R?).
From wikipedia (5-HT3 receptor - Wikipedia):
Researchers compared acute and persistent pain responses in wild-type and mutant (lacking the 5-HT3R-A subunit) mice.
(The 5-HT3 Subtype of Serotonin Receptor Contributes to Nociceptive Processing via a Novel Subset of Myelinated and Unmyelinated Nociceptors)
The authors conclude:
This got me interested in whether any 5-HT3R antagonists has been investigated as treatments for migraines.
I was able to locate some research, but it was limited largely by the toxic effects of the experimental treatments.
https://www.ncbi.nlm.nih.gov/pubmed/2045832
https://www.ncbi.nlm.nih.gov/pubmed/10563226
https://www.ncbi.nlm.nih.gov/pubmed/15515404
Curious what everyone else thinks. Please post any thoughts and studies you have to advance the conversation.
I'm still trying to sort out the differentiation of different serotonin "receptors", what agonizes and antagonizes them respectively, and what we know about the energetic state of the cell potentiates their respective affinities.
Virtually without question, but with some potential exception to receptor-specificity, serotonin has been implicated in the initiation of hibernation in animals:
Brain serotonin metabolism in hibernation. - PubMed - NCBI
Induction of unseasonable hibernation and involvement of serotonin in entrance into and maintenance of its hibernation of chipmunks T. asiaticus. - PubMed - NCBI
Does serotonin play a role in entrance into hibernation? - PubMed - NCBI
Same with melatonin, which seems to regular glucose homeostasis (insulin resistance), fat accumulation in preparation and endurance of hibernation, along with regulating sensitivity to light:
Plasma melatonin concentrations in hibernating marmots: absence of a plasma melatonin rhythm. - PubMed - NCBI
Melatonin modulates glucose homeostasis during winter dormancy in a vespertilionid bat, Scotophilus heathi. - PubMed - NCBI
This got me to thinking about the role of serotonin in mediating torpor/"hibernation" in animals, along with histamine and melatonin, modified sensitivity to light, sound, pain, and brain inflammation. It seems logical that increased serotonin may play a role in the reclusive, irritability that is experienced by many individuals chronically, especially those suffering from migraines (hyper-sensitivity of 5HT3R?).
From wikipedia (5-HT3 receptor - Wikipedia):
As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium (Na), potassium (K), and calcium (Ca) ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The rapidly activating, desensitizing, inward current is predominantly carried by sodium and potassium ions.[2] 5-HT3 receptors have a negligible permeability to anions.[1] They are most closely related by homology to the nicotinic acetylcholine receptor.
Researchers compared acute and persistent pain responses in wild-type and mutant (lacking the 5-HT3R-A subunit) mice.
(The 5-HT3 Subtype of Serotonin Receptor Contributes to Nociceptive Processing via a Novel Subset of Myelinated and Unmyelinated Nociceptors)
We next examined the animals in a model of persistent pain using the formalin test. In this paradigm, a dilute formalin solution is injected into the plantar surface of the hindpaw, and pain-related behavior (licking) is scored in two phases (for review, see Tjølsen et al., 1992). The first phase (∼0–10 min) is produced by direct activation of nociceptors and therefore provides a measure of acute chemical pain. The second phase results in part from a delayed inflammatory response in the injected paw and thus serves as a model of persistent pain resulting from tissue injury. Consistent with acute pain being intact in null mutant animals, we found that first-phase pain behavior did not differ in wild-type and mutant mice. In contrast, the second phase of pain behavior was significantly reduced in the mutant animals, indicating that 5-HT3Rs are important contributors to the nociceptive circuits that produce persistent pain (Fig. 3 a).
As for the behavioral profile, formalin evoked two phases of dorsal horn neuronal firing as shown previously in rats (Dickenson and Sullivan, 1987). The first phase consisted of an immediate increase in the firing rate that lasted for ∼2 min; there was no difference in the total number of spikes evoked in the first phase (0–10 min) between wild-type (mean ± SEM; 1236 ± 473) and mutant (1770 ± 617) mice (Fig.3 b,c). After a quiescent period, the wild-type mice exhibited a second phase of firing in which there was a marked increase in total spikes (4082 ± 1726), which mirrored the second phase of pain behavior. Consistent with the observed deficit in second phase pain behavior in null mutant mice, the magnitude of neuronal firing during the second phase in the knock-out animals was dramatically reduced (784 ± 410; p = 0.0175).
Finally, to identify the contribution of peripheral versus central 5-HT3Rs to sustained formalin-evoked pain behaviors, we used a pharmacological approach to inhibit receptor function in specific sites. We found that peripheral (intraplantar) injection of the 5-HT3R antagonist ondansetron reduced second, but not first, phase pain behavior in wild-type mice (Fig. 4 a). Because 5-HT3Rs are also found on the central (spinal) terminals of primary afferents and on dorsal horn interneurons (Hamon et al., 1989; Kia et al., 1995), we also examined the effect of ondansetron administered directly into the CSF (intrathecally). As observed after peripheral injection, intrathecal ondansetron dose dependently suppressed the second-phase paw-licking behavior in the formalin test (Fig. 4 b) but had no effect on the first (acute pain) phase (data not shown). These pharmacological results indicate that the reduced second-phase formalin behavior in the knock-out mice likely reflects loss of peripheral and central (spinal) 5-HT3R activity (Oyama et al., 1996)
As predicted, despite the differences in pain behavior, the edema produced by intraplantar serotonin did not differ in mutant and wild-type mice (Fig. 5). Paw injections of the 5-HT3R agonists mCPBG (1.0 μg/10 μl) or 2-methylserotonin (10 μg/10 μl) also produced intense paw licking in the wild-type mice. Importantly, however, the 5-HT3R agonists did not evoke significant paw swelling in either wild-type or null mutant mice (Fig. 5). Together, these results indicate that, when serotonin is released in the setting of tissue injury, it contributes to nociceptive processing and edema, but only the former is influenced by activation of the 5-HT3R.
The authors conclude:
Release of serotonin in the setting of injury thus has multiple consequences. Serotonin directly activates nociceptive afferents to increase the barrage of impulses transmitted to the spinal cord, resulting in an increase in behaviors indicative of pain. It also contributes to peripheral neurogenic inflammation, via activation of small-diameter peripheral afferents and release of proinflammatory peptides, such as SP from peripheral terminals. The latter induces extravasation of proteins from postcapillary venules, which in turn contributes to peripheral edema (Lembeck et al., 1982). The contributions of serotonin to nociception–pain and swelling, however, are readily dissociable according to the receptors that are activated. We found that peripheral injection of serotonin produced both pain behavior and swelling of the hindpaw in wild-type mice, but only the former was reduced in the 5-HT3R null mutant mice.
This got me interested in whether any 5-HT3R antagonists has been investigated as treatments for migraines.
I was able to locate some research, but it was limited largely by the toxic effects of the experimental treatments.
https://www.ncbi.nlm.nih.gov/pubmed/2045832
https://www.ncbi.nlm.nih.gov/pubmed/10563226
https://www.ncbi.nlm.nih.gov/pubmed/15515404
Curious what everyone else thinks. Please post any thoughts and studies you have to advance the conversation.
I'm still trying to sort out the differentiation of different serotonin "receptors", what agonizes and antagonizes them respectively, and what we know about the energetic state of the cell potentiates their respective affinities.