October 2015 Blog with Durk and Sandy

Because of the need to prepare our income taxes, this may be the shortest issue of the year. You can thank Uncle Assam for the loss of content. Back next month with a regular issue, assuming Uncle Assam doesn’t have something new and time-consuming for us (a big “if” these days). Just think of all the extra work piled onto doctors these days at the point of Uncle Assam’s guns and you can’t help but wonder that anyone wants to be a doctor anymore. The people making all this extra work are dangerous and are a direct threat to our health and longevity. Don’t elect new “better” people who want to do those jobs, get rid of those jobs! OK to elect people who truly want to get rid of those jobs, but watch out, lying is almost ubiquitous among the political class. Example: Gov. Sandoval of Nevada lied and lied about reducing taxes and is pushing for more and more of them. We believe that this man is a true SOCIOPATH. He doesn’t care what it costs to innocent bystanders for him to pursue what politically benefits himself. Something seems horribly amiss, when your political class is populated (mostly) by sociopaths.

Appetizers

Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughters, and jests, as well as our sorrows, pains, griefs, and tears... These things that we suffer all come from the brain...Madness comes from its moistness.

—Hippocrates(*)

The brain has to model everything it encounters, including itself. ...In that sense, the self is just a representation maintained in the brain, just like any other representation that we have of objects in the world.

—Jacob Mohwy, Monash University, Melbourne, Australia (from an interview by Anil Ananthaswamy, author of The Man Who Wasn’t There, Dutton, 2015)

To open a shop is easy, to keep it open an art.

—a proverb from the far East (probably China), no date given

(Comment: You have to wonder where it was and when that opening a shop was easy. It sure isn’t easy most places in the USA of 2015. On the way up, one supposes, as in the rise of the U.S. and the Roman Republic, it was easy to open a shop, but not on the way down in the U.S. and the Roman Empire after they passed the Republic phase. Julius Caesar ended the Roman Republic by declaring himself the Dictator, while in the U.S. it happened more quietly because no one was honest enough to declare the Republic kaput. According to the World Bank, the USA is now down to #40 in the ease of starting a new business. There are now more small businesses dying than being born.)

If I return to earth in another life, I hope it’s not during a Republican administration.

—Timothy Leary

[Dr. Leary never met Barack Hussein Obama.]

If we wanted to regain freedom, we were forced to strike. We told the Soviets that you can enter with your tanks if you wish. Then, we will put flowers in the guns of those tanks and your soldiers will sooner or later be forced to open the tanks and get out and get some air. When they are out, our girls will kiss them to death. However. we are not going to work for you anymore.

—Lech Walesa, PEACE 1983

[Ah, it’s the bonobo strategy of peace, trading sex for aggression. It works for the bonobos and it appears to have worked for Poland.]

EGCG AND CAPSAICIN SHOWN TO HAVE POWERFUL ANTICANCER EFFECTS

Catechin (EGCG) and activators of the TRPV1 receptor have been recently shown to have, in combination, very powerful anticancer effects in cell culture and in a mouse model of metastasis and ought to be tested for pain. The combination was 10-100 times as effective against cancer as either agent alone.(Morre & Morre, 2006)

• Morré, Morré . Catechin-vanilloid synergies with potential clinical applications in cancer. Rejuvenation Res.9(1):45-54 (2006).

 

TAURINE INCREASES HIPPOCAMPAL NEUROGENESIS INCREASING STEM AND PROGENITOR CELL PROLIFERATION AND INCREASING THE SURVIVAL OF NEWBORN NEURONS

Neurogenesis, the process of creating new neurons from stem cells, includes the maturation of the new neurons in which the neurons compete with one another for survival. Incredibly, a new paper (Bian, 2015) has now reported the discovery of some details of this competition.

They studied dendritic spines (the structures that provide important biochemical and electrical compartmentalization within neurons). Neurogenesis includes rapid spinogenesis. Here, the authors explain a hypothesis that new spines (mostly thin) underlie memory acquisition, while mature spines (mostly mushroom shaped and stubby) contribute to memory consolidation and storage. The authors found through their experiments that the small proportion of new neurons that were enriched in beta catenin were the ones that survived the pruning process that follows neurogenesis, while the ones with less beta catenin died by apoptosis. Interestingly, the neurons surrounding the beta catenin-enriched survivors were most likely to die. The authors ascribe this to “local competition for limited resources.”

Environmental enrichment, known to increase neurogenesis, also (according to the authors) accelerates spine pruning. “In the PFC [prefrontal cortex] and hippocampus...new memories are constantly formed and unconsolidated ones removed throughout life, a few synapses at a time, resulting in individualized spine dynamics and sustained circuit plasticity.” The authors also explain how enhanced or reduced expression of genes for spinogenesis can result in neurological disorders, including autism and schizophrenia. In fact, in another paper by different scientists (Yi, 2015), an autism-linked mutation was discovered (inherited maternally) that causes excessive dendritic spine development in the brain. It is interesting to note that one of the autism spectrum disorders, Asperger’s syndrome, actually shows some evidence for beneficial effects in some individuals. Though there may be deficiencies in recognizing faces, for example, there seem to be countervailing advantages such as enhanced sensory abilities (for example, the ability to recognize different colors) and possibly increased creativity. (A guy we know who has the syndrome suggests that the best game “trackers” would be Asperger’s because of superior ability to pick out the bent blades of grass and faint footmarks that you have to be able to track.) If so, this may explain why this gene hasn’t disappeared into the trash bin of evolutionarily dumped genes but has remained around, benefitting some and being a disaster for others, particularly for those who inherit two alleles for the trait rather than just one. Interestingly, Nobel Prize winners in mathematics and chess grandmasters disproportionally have the Aspberger form of autism.

But, getting back to neurogenesis, there are a number of nutrients that are known to increase neurogenesis, including resveratrol (found in red wine, cocoa, green tea), EGCG (particularly enriched in green tea), curcumin (found in turmeric root), and taurine, among many many others. Taurine, for example, has been found to increase hippocampal neurogenesis in aging mice (Gebara, 2015). “We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors.” “Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis.” This is a very impressive benefit from ingesting adequate amounts of taurine, which is a sulfur-containing amino acid not incorporated into proteins; it is found in large amounts in the brain, but also in the liver and kidney. Its concentration in the brain decreases with aging. The fact that taurine increases the stem cell pool is particularly exciting, as the renewal of the stem cell pool is limited in adults.

• Gebera, Udry, et al. Taurine increases hippocampal neurogenesis in aging mice. Stem Cell Res.14:369-79 (2015).
• Bian, Miao, et al. Coordinated spine pruning and maturation mediated by inter-spine competition for cadherin/catenin complexes. 162:808-22 (2015).
• Yi, Berrios, Newbern, et al. An autism-linked mutation disables phosphorylation control of UBE3A. 162:795-807 (2015).

 

NEW SCIENTIFIC DISCOVERY: PREDATOR V. PREY POWER LAW MIGHT PREDICT WHAT HAPPENS TO LARGE POLITICAL ECOSYSTEMS SUCH AS THE UNITED STATES

Sometime very soon: You enter your library stacks and put American History next to “The Road to Serfdom” and file it under “The Ashheap of History.” Have you just entered “the Twilight Zone” or is the United States, a large ecosystem, governed by the same rules of the predator vs. prey Power Law shown to apply to all large ecosystems and which predicts that the biomass pyramid becomes increasingly bottom heavy (more prey, fewer predators) at higher biomass. See our analysis in next issue of this newsletter. REF: Hatton, McCann, Fryxell, et al. The predator-prey power law: biomass scaling across terrestrial and aquatic biomes. Science. 349(6252) (4 Sept. 2015).

 

INCOHERENCE IN GOVERNMENT ADMINISTRATIVE REGULATIONS—THEN AND NOW A PROPHECY FROM THE PAST MIGHT POINT TO THE OUTCOME OF OUR NEXT ELECTION

In a recent online post (Sept. 1, 2015) entitled “Government Decoherence and Its Discontents” by Philip A. Wallach, Mr. Wallach discusses his view that decoherence (we think the proper word is incoherence) is a natural outcome of tendencies in liberal, pluralist democracy. He notes that this was the prophecy of Carl Schmitt, who was a political scientist/economist during the Weimar Republic of Germany. Schmitt’s book Legality and Legitimacy, “diagnosed legislature-dominated liberal orders as utterly incapable of meeting the demands of crises, and perhaps even the tasks of economic management for which they were taking responsibility” at the time he wrote this. “Lack of legislative dexterity would lead liberal societies to embrace what Schmitt called an ‘administrator’ form of government based on ad hoc decrees designed to respond to the needs of the moment.” This incoherence of policy would lead to an erosion in citizens’ belief in the congruence between “law and statute, justice and legality, substance and process,” with a loss of legitimacy. “In Schmitt’s oracular telling, this will lead to total dissolution of the state or the rise of some more viable alternatives rooted in a single leader’s plebiscitary connection with the people.” Indeed, Adolf Hitler proved to be that single leader prophesied by Schmitt. We know how that ended ....

We do not currently appear to have a Hitler on the horizon, but interestingly there is a candidate for President who proposes policies designed to meet the needs of the moment and who speaks a language of frankness that attracts people looking for somebody who is not afraid to say it like it is, even in an uncouth manner disrespectful of the political class. That might not end well, either...

Your Privacy Is Totally Obliterated in the Next Version of WINDOWS

SORRY. THIS IS NOT A JOKE. 

PLEASE PAY ATTENTION IF YOU PLAN TO USE THE NEXT VERSION OF WINDOWS, WINDOWS 10

We regret to inform you of the following. If you use the next version of WINDOWS, you will notice in the Microsoft Privacy Statement (updated July 2015), this statement under “REASONS WE SHARE PERSONAL DATA,” third paragraph under “Full text,:” “...we will access, disclose and preserve personal data, including your content (such as the content of your emails, other private communications or files in private folders), when we have good belief that doing so is necessary.” After this incredible statement, Microsoft gives four possible reasons for believing (in good faith!) it to be necessary, number one being: “1. comply with applicable law or respond to valid legal process, including law enforcement or other government agencies.”

Draw your own conclusions about (1) why Microsoft included this statement in their “privacy” statement, (2) what “government agencies” might want access to data such as what is in your private emails, and (3) is there any privacy left in relation to the government? You use the next version of WINDOWS at your own risk.

https://github.com/WindowsLies/BlockWindows

Worse yet, Microsoft is pushing spyware updates into Windows 7 and 8 installations. See also other comments in the above thread. Look especially at the comments entered at the following times by these parties:

https://www.schneier.com/blog/archives/2015/09/understanding_s.html

September 9, 2015 5:54 AM by Curious

September 4, 2015 6:36 PM by Peanuts

September 4, 2015 12:05 AM by Peanuts on History of the L0pht:

http://www.theregister.co.uk/2015/09/01/microsoft_backports_data_slurp_
to_windows_78_via_patches/

Alien Jerky • September 2, 2015 10:01 AM (on schneier.com)

Peanuts • September 3, 2015 12:47 AM (on schneier.com)

Thomas_H • September 3, 2015 2:56 AM (on schneier.com)

We suspect that these spyware additions to Windows happened following an offer from the US government that Bill Gates couldn’t refuse… There will undoubtedly be more 4th Amendment trashing to come. Great source of security info:

https://www.schneier.com/

But on to life enhancing and fun stuff…

 

RECIPE FOR A PEACEFUL CIVILIZATION? COULD THIS KNOWLEDGE SAVE THE WORLD?

We interrupt this tax preparation waste of productive effort for a flash from the scientific literature on what may be an excellent recipe for the peaceful, productive society we all want. This paper (Rilling, 2012) presents what the authors claim is the first ever [we’ve certainly never seen anything like this before] comparison of chimpanzee and bonobo brains using diffusion tensor imaging, supplemented with a voxel-wise analysis of T3-weighted images to specifically compare neural circuitry implicated in social cognition. As you know, the bonobos have largely substituted sex and play for aggressive violence in social interactions, while chimps are more like humans, with plenty of aggressive violence in social interactions.

Here it is: “We find that bonobos have more gray matter in brain regions involved in perceiving distress in both oneself and others, including the right dorsal amygdala and right anterior insula. Bonobos also have a larger pathway linking the amygdala with the ventral anterior cingulate cortex, a pathway implicated in both top-down control of aggressive impulses as well as bottom-up biases against harming others. We suggest that this neural system not only supports increased empathic sensitivity in bonobos, but also behaviors like sex and play that serve to dissipate tension, thereby limiting distress and anxiety to levels conducive with prosocial behavior.” (Rilling, 2012)

WOW! You’d think that findings such as this would receive a lot of attention, but have you seen this anywhere in the press??? This could be a formula to save the world because human aggression, particularly the coercive type, is wrecking havoc.

Imagine having the opportunity to find out how the brains of your potential mates or potential business associates look as compared to the bonobo brain? We’d definitely choose people with those traits over what you usually get. People are dangerous and, in business, the difficulty of distinguishing liars, sociopaths, and criminals from the others is such that you make mistakes and may have to pay a high cost for those mistakes. We’ve had plenty of experience with that. It has cost us a lot.

Our thanks to the authors, whose names we give in full as the heroes that they are:

James K. Rilling, Jan Scholz, Todd M. Preuss, Matthew F. Glasser, Bhargav K. Errangi, and Timothy E. Behrens. Differences between chimpanzees and bonobos in neural systems supporting social cognition. Soc Cogn Affect Neurosci. 7:369-79 (2012).

Correspondence should be addressed to: James K. Rilling, Ph.D., Associate Professor, Dept. of Anthropology, Dept. of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322 E-mail: jrillin@emory.edu [email as given in the paper; don’t know why the “g” was dropped from jrillin.]

Negative and Competitive Social Interactions Are Related to Heightened Proinflammatory Cytokine Activity

We may have reported this before, but it is so relevant to the matter of bonobo vs. chimp style social relationships, that we mention it again here. A recent study (Chiang, 2012) found that, among 120 healthy young adults who kept daily diaries for 8 days that noted positive, negative, and competitive social interactions, the negative social interactions and those involving hostile competition (not ordinary leisure time competitive activities) led to significantly higher inflammatory cytokine levels. (The volunteers were tested within 4 days of completing the daily diaries, but the effect of social interactions that took place in the intervening period could not be determined.) It would be interesting to measure the level of proinflammatory cytokines in bonobos as compared to chimpanzees.

• Chiang, Eisenberger, et al. Negative and competitive social interactions are related to heightened proinflammatory cytokine activity. Proc Natl Acad Sci U S A.109(6)1878-82 (2012).

(*) Comment on Hippocrates’ Notion of the Brain Circa 400 BC (see quote above)

It is stunning how much had been figured out so long ago by the most learned. “Moistness” in Hippocrates’ quote probably refers to the cholinergic nervous system, which when overactive, causes profuse sweating and oodles of saliva (don’t know whether the brain itself is “moist”). This visible moistness is associated with conditions such as epilepsy, dissociative disorders, schizophrenia, and other states that could be thought of as madness. Interestingly, compensatory hypersensitivity to the cholinergic nervous system (Scinto, 2008) under conditions where cholinergic signaling is deficient speculates Sandy and Durk may be involved in the development of brain disorders such as Alzheimer’s and Parkinson’s diseases, both of which can be accompanied by dementia, with AD being the most severe, of course. Thus, the cholinergic system may play a complex role in the development of Alzheimer’s and Parkinson’s, as the following reports on the negative impact of anticholinergic drugs and the beneficial effects of cholinergic agonists in a model of cholinergic denervation show.

• Pupillary cholinergic hypersensitivity predicts cognitive decline in community dwelling elders. Neurobiol Aging.29:222-30 (2008).

 

A Hypothesis About Alzheimer’s Disease, Its Cause and a Possible Method of Treatment, and Experimental Support for the Hypothesis

by Sandy Shaw

One hypothesis shared by me and probably some others about AD is that it is the ultimate dissociative disorder, with the connections between various areas of the brain being destroyed, leaving behind the originally connected material (memories, stored data, etc.), in a state where it cannot be accessed by other brain areas (some scientists including myself wonder whether it might theoretically be possible to reconstruct the connections and retrieve this material. If that is possible, it is likely, I think, to be limited to a certain critical period of time as neurons die when they are not active.)

If the hypothesis is correct, then one prediction is that the restoration of connections in a model of cholinergic denervation might be a reasonable model for Alzheimer’s disease and a possible correction. Thus, a 2010 paper (Kampen and Eckman, 2010) is right on point. Here, the researchers studied the use of cholinergic agonists to restore hippocampal neurogenesis and improve cognition in a model of cholinergic denervation (the very connections the hypothesis would suggest are missing or damaged). The authors report “the effects of various cholinergic compounds on indices of hippocampal neurogenesis, demonstrating a significant induction following pharmacological activation of [cholinergic] muscarinic M1 receptors, located on hippocampal progenitors in the adult brain [of female Sprague-Dawley rats].” The chemicals studied included nicotine (which is an agonist, that is, it activates, nicotinic-cholinergic receptors and the cholinesterase inhibitor physostigmine, the nonselective cholinergic agonist carbachol, the muscarinic agonist oxotremorine, or their vehicle.

Results showed that the maximal induction was observed following the highest dose of oxotremorine, the muscarinic agonist. Only lower doses of carbachol elevated cell proliferation in the dentate gyrus (an area of neurogenesis), and the CHOLINESTERASE INHIBITOR physostigmine triggered a modest, but significant, elevation in the production of new neurons from progenitors. As the authors explain, “...we have shown that selective activation of muscarinic receptors is capable of triggering an induction of cell proliferation not only in the DG [dentate gyrus], but also the CA1 region of the hippocampus, an area of severe neuronal loss in AD [Alzheimer’s disease].” “...oxotremorine-induced increases in BrdU-positive cell counts [neurogenic cells] are likely to reflect an effect on cell proliferation rather than an indirect effect on cell survival.” “...impairments in cell proliferation, in a model of basal forebrain cholinergic cell loss are counteracted by chronic muscarinic activation. This restoration of cell proliferation is accompanied by a time dependent increase in the number of newly generated cells expressing neuronal markers and by a reversal of cognitive deficits characteristic of this model.”

• Kampen, Eckman. Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation. 58:921-9 (2010).

 

THE MEXICAN SIESTA:GOOD FOR YOUR HEALTH, NOT JUST FOR A NAP AFTER LUNCH

HYPOTHESIS: Sandy thinks that the Mexican siesta, where people sleep for a while following a heavy lunch, is linked to the pulsatile release of prostaglandin D2 (also released by the niacin flush as a pulse. See Sandy’s paper on that subject if interested in technical discussion, available in three parts at the Life Enhancement magazine for July, August, and September, www.life-enhancement.com). The Mexican foods found in a lunch are generally high in hot chili peppers that contain capsaicin, which activates the TRPV1 receptor (Lee, 2015). That receptor does a number of interesting things, such as reducing the risk of obesity and diabetes (Lee, 2015), reducing pain (Origoni, 2014), reducing inflammation (Zhao, 2013) generally, as well as being a major sleep-inducing signal (hence the siesta).

A major part of the pathway by which TRPV1 accomplishes these effects is via the pulsatile release of the prostaglandin PGD2, which suppresses the chronic release of PGD2 that has proinflammatory effects in diseases such as Alzheimer’s disease and also reduces the release of PGE2, an inflammatory prostaglandin associated with hyperalgesia (severe pain). (Ndengele, 2008) (Also see Sandy Shaw’s paper on the niacin flush in the section on Alzheimer’s disease that appeared in the August issue of the LIFE ENHANCEMENT magazine online at www.life-enhancement.com.)

• Lee, Jung, Kim, et al. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J.29:3182-92 (2015).
• Origoni, Maggiore, et al. Neurobiological mechanisms of pelvic pain. Biomed Res Int. 2014:903848. doi: 10.1155/2014/903848. Epub 2014 Jul 8 (2014).
• Zhao, Ching, Kou, et al. Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-alpha-induced inflammation in macrophages: role of liver X receptor alpha. Mediators Inflamm. 2013:925171. doi: 10.1155/2013/925171. Epub 2013 Jun 26 (2013).
• Ndengele, Cuzzocrea, et al. Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J. 22:3154-64 (2008).

 

RELIEF FROM INTRACTABLE PAIN BY ENHANCING THE EFFECTS OF OPIATES WITH NATURAL PRODUCTS

People who are having intolerable pain, such as those with far advanced cancer, have the problem both of getting opiates to treat their pain and of the fact that opiates have limits in their effectiveness in really severe pain. Here are a couple of suggestions for what can be done with simple easily available totally legal no prescription needed supplements that have been shown to enhance the effectiveness of morphine.

CHOLINE ENHANCES THE EFFECT OF MORPHINE

Choline and acetylcholine agonists have been shown in animal studies to have antinociceptive (to decrease pain) effects. (Rowley, 2010) (Serrano, 1994) (Yong-Ping, 2011). As described in Rowley, 2010, choline provided (in mice) “moderately effective analgesic via activation of alpha7 nicotinic acetylcholine receptors.” Cholinesterase inhibitors (such as galantamine, which is active at the alpha7 nicotinic acetylcholine receptor) are known to have analgesic activity (Rowley, 2010) Importantly, the administration of choline (2 mg/kg) with morphine (0.165 mg/kg) significantly increased the pain-killing efficacy of morphine in the late phase but not in the early phase (Wang, 2005).

Moreover, the combination of cholinergic agonists and aspirin provided significantly enhanced relief of pain in a model where mice received painful acetic acid intraventricular injections. (Yong-Ping, 2011) The same effect would be expected with the combination of cholinergic agonists and other NSAIDS.

In addition, another report (Serrano, 1994) showed in rats and mice subjected to painful acetic acid and to the tail flick test (where the animal removes its tail from a hot plate when it gets painful), that the antipain effects of taurine required peripheral cholinergic mechanisms. In studies done before (Serrano, 1994), the authors note, taurine prevented the development of tolerance to a centrally administered enkephalin analog (enkephalin is an endogenous opioid).

There is some evidence that cholinergic agonists and TRPV1 (vanilloid) receptors have antinociceptive effects (Origoni, 2013), and the combination is synergistic. (ref vanished) The TRPV1 (vanilloid) receptor is sometimes called the capsaicin receptor because hot peppers containing capsaicin activate that receptor, manifested by sweating and skin flushing. It is also activated by vanillin, the major constituent of vanilla. Incidentally, you can get vanillin by buying “synthetic vanilla” at the supermarket; as the major constituent of vanilla, it tastes a lot like vanilla but has to be labeled as “synthetic vanilla.” It has recently been discovered that niacin activates the TRPV1 receptor, explaining at least in part the flush you get from hot peppers (Ma, 2014). This suggests (but we have not seen a test of this) that niacin might act to increase the antipain effects of TRPV1 agonists and combinations of cholinergic and TRPV1 agonists.

REDUCING PAIN BY INHIBITING TRPV1, THE CAPSAICIN RECEPTOR, WITH OTC DRUG

TRPV1 is a pain detecting receptor, but desensitizing it, by for example eating a lot of hot chili, is a way to reduce pain. It has been discovered that the TRPV1 receptor can be downregulated (desensitized) by mu opioid drugs. Mu opioid drugs includes morphine and fentanyl, but interestingly there is an OTC drug that activates the mu opioid receptor that will do the same thing to the TRPV1 receptor. We refer to loperamide, a PERIPHERAL mu opioid receptor agonist that does not pass the blood brain barrier and, hence, cannot cause addiction, respiratory depression, itching, and other side effects of central mu opiate activity. Loperamide is used to treat diarrhea, firming up feces, and unsurprisingly a side effect of taking too much is constipation. Use according to label instructions.

A paper (Butelman, 2004) reports that rhesus monkeys exposed to capsaicin to induce pain (assessed by a tail withdrawal assay), “loperamide (0.1-1 mg. /kg sc) acting as a peripherally selective mu-agonist after sc [subcutaneous] administration, produced a prevention of topical capsaicin-induced allodynia [pain induced stress].” However, loperamide did not prevent pain induced by heat, presumed to be a centrally mediated effect of mu agonist. Fentanyl, a mu agonist centrally active opioid, was more effective than loperamide at REVERSING pain induced by capsaicin and could PREVENT pain induced by both capsaicin and heat. Peripheral mu receptor agonists (such as loperamide) are reported to be particularly effective in decreasing pain due to inflammatory hypersensitivity (Endres-Becker, 2007)

• Butelman, et al. Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates.J Pharmacol Exp Ther.311:155-63 (2004).
• Endres-Becker, et al. Mu opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol Pharmacol.71:12-8 (2007).
• Kumar, Priyadarsini, et al. Inhibition of peroxynitrite-mediated reactions by vanillin. J Agric Food Chem.52:139-45 (2004).
• Origoni, Maggiore, et al. Neurobiological mechanisms of pelvic pain. Biomed Res Int. 2014:903848. doi: 10.1155/2014/903848. Epub 2014 Jul 8. (2014).
• Ying-Pong et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain.15:858- 65 (2011).
• Rowley, et al. Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain. Br J Anaesth.105(2):201-7 (2010).
• Ma, Lee, Mao, et al. Nicotinic acid activates the capsaicin receptor TRPV1—a potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol. 14(6):1272-80 (2014).

 

CAUSE OF CHRONIC ITCH IDENTIFIED CHRONICALLY HIGH PROSTAGLANDIN D2 LEVELS MAY BE INVOLVED AND SUGGEST POTENTIAL TREATMENTS

Lipocalin-2 was shown to be upregulated by astrocytic STAT 3 and to be crucial for chronic itch (Shiratori-Hayashi, 2015). In experiments in mice with atopic dermatitis, “...conditional disruption of astrocytic STAT 3 suppressed chronic itch, and pharmacological inhibition of spinal STAT 3 ameliorated the fully developed chronic itch.” As lipocalin-type prostaglandin D2 and prostaglandin E1 are isoprostanes involved with inflammation (acting either as a proinflammatory mediator or, if released in a pulse, as an antiinflammatory mediator), they may be involved in this process, Sandy hypothesizes. The researchers found that the reactive astrocytes might be maintained in lesioned skin (such as skin that has been scratched repeatedly) by TRPV1 receptors (the pain receptors that are activated by capsaicin, but can be desensitized by chronic activation by capsaicin). See discussion of TRPV1 receptors below, which indicate that pulsatile prostaglandin D2 is indeed involved in the process by which capsaicin can be used to reduce itching and pain.

• Shiratori-Hayashi, Koga, et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med.21(8):927-31 (2015).

 

NATURAL PRODUCT INHIBITORS OF STAT3

There are a number of them. Most likely, a combination will work better than just one if you want to suppress a nasty itch. They include curcumin, resveratrol, piceatannol (an analog of resveratrol), caffeic acid, capsaicin (possibly make it worse at first), betulinic acid, ursolic acid, oleanolic acid, gamma tocotrienol, and many others (Miklossy, 2013)≥

• Miklossy et al. Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov. 12(8):611-29 (2013).

 

SEXUAL EXPERIENCE PROMOTES ADULT NEUROGENESIS

Environmental enrichment and exercise, as well as a large number of natural products can increase neurogenesis. SEX is another way to get it. A study with sexually experienced adult male rats were exposed to an acute dose of sex by having access to a receptive female for one occasion or were exposed to a chronic dose by having access to a receptive female once daily for 14 days. (Over the 14 days, the males were generally given a new female each time but because there were only a limited number of females, occasionally they got one they’d had before, but the researchers say that it made no difference in sexual behavior.) Videos were analyzed for mounts, intromissions, and ejaculations.

The results showed that circulating corticosterone levels were elevated in male rats after sexual experience compared to naive controls (did not engage in sex, but were left undisturbed in their cages), although these levels were no longer increased following chronic sexual exposures. Whereas most stresses that increase corticosterone levels increase anxiety and decrease neurogenesis, neither of these took place in the sexually experienced rats, which were less anxious than naive controls and had increased neurogenesis and the growth of dendritic spines. It was the difference between aversive stressors and rewarding ones that produced the alteration in the outcomes of anxiety and neurogenesis. The authors point to exercise as a similar positive stress that increases corticosterone levels but reduces anxiety and enhances neurogenesis.

The researchers also point out that “neuromodulators altered with sexual experience and known to influence adult neurogenesis, like opiates or dopamine, seem plausible [as possible mediators of the beneficial effects of sexual experience], as does oxytocin, a neuropeptide that buffers the brain and body against some of the adverse consequences of stress hormones.”

• Leuner, Glasper, Gould. Sexual experience promotes adult neurogenesis in the hippocampus despite an initial elevation in stress hormones. PLoS One.2010 Jul 14;5(7):e11597. doi: 10.1371/journal.pone.0011597. (2010).

 

The Flush Caused By Activation of TRPV1 By Agonists Like Capsaicin Appears to Be PART OF the Niacin Flush!

A speculation: While TRPV1 receptors are pain receptors that are activated by capsaicin, they can be desensitized by chronic treatment with capsaicin. This desensitization may involve, Sandy speculates by pulsatile release of PGD2, prostaglandin D2, which seems to be involved as a stop signal for inflammation in a large variety of inflammatory diseases. (See Sandy Shaw’s paper on the niacin flush (actually it is on prostaglandins and their role in inflammatory diseases) in the July, Aug., Sept. 2015 issues of Life Enhancement on the web at www.life-enhancement.com.

One thing that makes me suspicious that a pulse of prostaglandin D2 (PGD2) might be involved here is that, when you eat a meal with hot spices, you sweat and feel hot for a short period, a cutaneous flush much like the niacin flush, which is caused by a pulsatile release of PGD2.

Serendipity Strikes Again!

The above two paragraphs (in the exact words as originally written) was typed into this newsletter on 8-30-2015. Later that very same day, Sandy found a paper in a search she requested that was conducted by Durk for her that reports (Ma, 2014) that nicotinic acid (niacin) activates the capsaicin receptor TRPV1 (in a slightly different way than capsaicin) and that the flush that results is part of the niacin flush. The rest is due to the release of a pulse of prostaglandin D2 produced by niacin’s HCA2 activation in Langerhans cells and keratinocytes of the skin. (Ma, 2014) However, I did not see anything in the Ma et al paper that rules out the release of pulsatile prostaglandin D2 by activation of the TRPV1 receptor. In fact, a search Durk did at my request on TRPV1 and PGD2 suggests that it is in fact a pulse of PGD2 that occurs as a result of TRPV1 activation that is responsible for the flush produced by TRPV1 agonists such as capsaicin. The “niacin flush” strikes again!!

Hence, it is not only the niacin flush that results from the pulse of prostaglandin D2, but the TRPV1 “hot spices” flush that (in part) results from it, revealing the importance of the antiinflammatory PGD2 pulse and its potential application to a large variety of inflammatory diseases.

• Ma, Lee, Mao, et al. Nicotinic acid activates the capsaicin receptor TRPV1—a potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol.34(6):1272-80 (2014).