Wednesday, July 24, 2013

Melzack & Katz, Pain. Part 17d: Stress, aging, and pain

The paper, Pain.

Part 17: The stress of it all Part 17b: Stress and adrenals Part 17c: Women, pain, and stress


Yesterday we delved into the topic of women and chronic pain - today, we'll delve into aging and stress and pain. The topic of aging and stress might keep us busy for a few days all by itself. 

The next paragraph under the topic of "Pain and stress" in Melzack and Katz's paper, in the section Beyond the Gate, is as follows: 

"Some forms of chronic pain may occur as a result of the cumulative destructive effect of cortisol on muscle, bone, and neural tissue. Furthermore, loss of fibers in the hippocampus due to aging reduces a natural brake on cortisol release which is normally exerted by the hippocampus. As a result, cortisol is released in larger amounts, producing a greater loss of hippocampal fibers and a cascading deleterious effect. This is found in aging primates71 and presumably also occurs in humans. It could explain the increase of chronic pain problems among older people."
What is cortisol?
Google answers, "..hydrocortisone: an adrenal-cortex hormone (trade names Hydrocortone or Cortef) that is active in carbohydrate and protein metabolism."

Here is the Wikipedia entry on
cortisol. It is a type of glucocorticoid. If it's active in metabolizing carbs and protein, we definitely don't want it to have any chance to digest our tissue or interact too much with our immune or neural pathways. Right?

What is glucocorticoid? 
Google answers, "..a steroid hormone that is produced by the adrenal cortex of animals; affects functioning of gonads and has anti-inflammatory activity."

Here is the wikipedia entry on glucocorticoid. That would be the upside, I guess. Good in small doses. 

Anyway, glucocorticoids are like fruit, and cortisol is like an apple, or specific kind of fruit. Got it now.. 
Reference 71 goes to Sapolsky's book, Why Zebras Don't Get Ulcers (full text). First, I'd like to meander a bit around Robert Sapolsky, the person and author. He's definitely worth a short meander.  

Here is a nice pic of him, sitting by a stream, by the look of things, a wild baboon behind him.

Robert Sapolsky spent 30 years or so going to Africa every year to spend months there, studying stress in a particular baboon troop. I love this guy. His autobiography, A Primate's Memoir, is one of the funniest books I've ever read about some very serious topics, including African politics, customs, cultures. Being alone there months on end conducting field research gave him plenty of imaginative leeway - every baboon ended up with a name and a personal relationship with Sapolsky, inside his own head at least. 

He is not only a prolific author but one of the world's foremost educative geniuses on the topic of stress, specifically, and the brain in general, in my opinion. Here is a link to an entire course he teaches on Human Behavioural Biology at Stanford, right on Youtube, free for everyone. I've sat through all 25 hours of this, some hours more than once. Check it out. If anyone can get anybody interested in the topic of the brain and stress, he can.

Here is a search of his lectures to do more specifically with stress. If you are bored (which is a kind of stress), this will keep you busy and entertained for days and days and days non-stop. 

About stress research in general
I love this section of Sapolsky's pdf on bioengineering, p. 132. 

"Suppose you wonder how the brain knows when to stop glucocorticoid secretion—when enough is enough. In a vague sort of way, everyone knew that somehow the brain must be able to measure the amount of glucocorticoids in the circulation, compare that to some desired set point, and then decide whether to continue secreting CRH or turn off the faucet (returning to the toilet tank model). The bioengineers came in and showed that the process was vastly more interesting and complicated than anyone had imagined. There are "multiple feedback domains"; some of the time the brain measures the quantity of glucocorticoids in the bloodstream, and sometimes the rate at which the level is changing. The bioengineers solved another critical issue: Is the stress-response linear or all-or-nothing? Epinephrine, glucocorticoids, prolactin, and other substances are all secreted during stress; but are they secreted to the same extent regardless of the intensity of the stressor (all-or-nothing responsiveness)? The system turns out to be incredibly sensitive to the size of the stressor, demonstrating a linear relationship between, for example, the extent of the drop in blood pressure and the extent of epinephrine secretion, between the degree of hypoglycemia (drop in blood sugar) and glucagon release. The body not only can sense something stressful, but it also is amazingly accurate at measuring just how far and how fast that stressor is throwing the body out of allostatic balance. 
"Beautiful stuff, and important. Hans Selye loved the bioengineers, which makes perfect sense, since in his time the whole stress field must have still seemed a bit soft-headed to some mainstream physiologists. Those physiologists knew that the body does one set of things when it is too cold, and a diametrically opposite set when it is too hot, but here were Selye and his crew insisting that there were physiological mechanisms that respond equally to cold and hot? And to injury and hypoglycemia and hypotension? The beleaguered stress experts welcomed the bioengineers with open arms. "You see, it's for real; you can do math about stress, construct flow charts, feedback loops, formulas. ..." Golden days for the business. If the system was turning out to be far more complicated than ever anticipated, it was complicated in a way that was precise, logical, mechanistic. Soon it would be possible to model the body as one big input-output relationship: you tell me exactly to what degree a stressor impinges on an organism (how much it disrupts the allostasis of blood sugar, fluid volume, optimal temperature, and so on), and I'll tell you exactly how much of a stress-response will occur. 
"This approach, fine for most of the ground that we've covered up until now, will probably allow us to estimate quite accurately what the pancreas of that zebra is doing when the organism is sprinting from a lion. But the approach is not going to tell us which of us will get an ulcer when the factory closes down. Starring in the late 1950s, a new style of experiments in stress physiology began to be conducted that burst that lucid, mechanistic bioengineering bubble.  
"A single example will suffice. An organism is subjected to a painful stimulus, and you are interested in how great a stress-response will be triggered. The bioengineers had been all over that one, mapping the relationship between the intensity and duration of the stimulus and the response. But this time, when the painful stimulus occurs, the organism under study can reach out for its mommy and cry in her arms. Under these circumstances, this organism shows less of a stress-response."
This has kind of messed up pain research, I think. Instead of trying to measure the psychophysical aspects of pain, the perception of it, the pain researchers who want to study more cut and dried material have consistently tried to pretend, or worse, insist that pain and nociception are the same thing. Because it has been more convenient to schmush the two things together, instead of holding them separately. 

Like ordering fruit salad, but being served a cut-up apple. Or going to the San Diego zoo to see animals, and finding nothing there but cows. 

I think stress research might be further ahead in some ways, if the complex psychosocial aspects of it have been recognized since the 50's, as Sapolsky suggests. Bear in mind, this is book is old, first published in 1994. 

Why there is nothing linear about the pain response of humans
"Nothing in that clean, mechanistic world of the bioengineers could explain this phenomenon. The input was still the same; the same number of pain receptors should have been firing while the child underwent some painful procedure. Yet the output was completely different. A critical realization roared through the research community: the physiological stress-response can be modulated by psychological factors. Two identical stressors with the same extent of allostatic disruption can be perceived, can be appraised differently, and the whole show changes from there."

Back to the Melzack & Katz reference

Sapolsky says (p 128 of this pdf)
"We know by now that, ideally, the hormones of the stress-response should be nice and quiet when nothing bad is happening, secreted in tiny amounts. When a stressful emergency hits, your body needs a huge and fast stress response. At the end of the stressor, everything should shut off immediately. And these traits are precisely what old organisms typically lack. 
"..sometimes the problem in aging is not enough of a stress-response. Predictably, in some realms, the problem is too much of a stress-response—either one turned on all the time, or one that takes too long to turn off at the end of a stressor. As an example, older individuals are impaired at turning off epinephrine, norepinephrine, or glucocorticoid secretion after a stressor has finished; it takes longer for levels of these substances to return to baseline. Moreover, even in the absence of the stressor, epinephrine, norepinephrine, and glucocorticoid levels are typically elevated in aged rats, nonhuman primates, and humans [aged late 70's, 80's] as well. 
"Do aged organisms pay a price for having these components of the stress-response turned on too often? This seems to be the case. As one example, which was discussed in the chapter on memory, stress and glucocorticoids inhibit the birth of new neurons in the adult hippocampus and inhibit the growth of new processes in preexisting neurons. Is the birth of new neurons and the elaboration of neuronal processes preferentially inhibited in old rats? Yes, and if their glucocorticoid levels are lowered, neurogenesis and process growth increase to levels seen in young animals."
Aging linked to glucocorticoid dysregulation occurs in salmon, and in mice, and by extension, in us too:
"When salmon spawn, regulation of their glucocorticoid secretion breaks down. Basically, the brain loses its ability to measure accurately the quantities of circulating hormones and keeps sending a signal to the adrenals to secrete more of them. Lots of glucocorticoids can certainly bring about all those diseases with which the salmon are festering. But is the glucocorticoid excess really responsible for their death? Yup. Take a salmon right after spawning, remove its adrenals, and it will live for a year afterward.

"The bizarre thing is that this sequence of events not only occurs in five species of salmon, but also among a dozen species of Australian marsupial mice. All the male mice of these species die shortly after seasonal mating; cut out their adrenal glands, however, and they too keep living. Pacific salmon and marsupial mice are not close relatives. At least twice in evolutionary history, completely independently, two very different sets of species have come up with the identical trick: if you want to degenerate very fast, secrete a ton of glucocorticoids."
I'm not very clear on how increased secretion of, and diminished control of glucocorticoids interacts with pain. Steroids are administered for pain, e.g., dexamethasone for cancer pain, or various kinds for arthritis. They suppress the immune system, inflammation.. right? But all sorts of funky things occur in the spinal cord, and microglia become involved. And stress, even if it's imaginary and blown out of all proportion and completely inconsequential in the long run, affects the parts of the brain that respond to stressors, because how does the internal regulation system (critter brain) know any better?  I confess, I have not looked deeply into this issue. There could be entire libraries of papers/books on just this topic alone.

This paper suggests that psychological stress enhances those little extracellular pathways discussed in the gliopathy paper, like ERK  

"These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress."

Alexander et al.; Stress Exacerbates Neuropathic Pain via Glucocorticoid and NMDA Receptor Activation. Brain Behav Immun. 2009 August; 23(6): 851–860. (full text)

Back to Sapolsky
There follows a discussion of sensitivity of the brain to elevated levels, negative feedback inhibition mechanisms that normally turn off production of glucocorticoids.

So what happens with aging?
"Why the failure of feedback regulation? There is a fair amount of evidence that it is due to the degeneration during aging of one part of the brain. The entire brain does not serve as a "glucocorticoid sensor"; instead, that role is served by only a few areas with very high numbers of receptors for glucocorticoids and the means to tell the hypothalamus whether or not to secrete CRH. In chapter 10, I described how the hippocampus is famed for its role in learning and memory. As it turns out, it is also one of the important negative feedback sites in the brain for controlling glucocorticoid secretion. It also turns out that during aging, hippocampal neurons may become dysfunctional. When this occurs, some of the deleterious consequences include a tendency to secrete an excessive amount of glucocorticoids—this could be the reason aged people may have elevated resting levels of the hormone, may have trouble turning off secretion after the end of stress, or may be dexamethasoneresistant. It is as if one of the brakes on the system has been damaged, and hormone secretion rushes forward, a little out of control."

Ah.... so, dysregulation starts with the hippocampus.

But here is the catch - Sapolsky, p 130:

"The elevated glucocorticoid levels of old age, therefore, arise because of a problem with feedback regulation in the damaged hippocampus. Why are neurons damaged in the aging hippocampus? It's glucocorticoid exposure, as was discussed in chapter 10."

Positive feedback loop? Uh-oh..

Top down stress = not good

Excess glucocorticoids suppress hippocampal neuroplasticity/neurogenesis and are associated with beta-amyloid protein deposit (associated with Alzheimer's) in the brain. Hippocampus might lose its ability to help the hypothalamus regulate glucocorticoid release and feedback restraint mechanisms via negative feedback mechanisms.

If you can keep that hippocampus hip, you might stay physiologically younger no matter how old you become in years.

OK... we have to take care of our hippocampus. Taking care of it will help us take care of the homeostatic mechanisms, i.e., the hypothalamus!

But that requires... exercise, right? Doesn't exercise = stress? Well, yeah, but it's bottom-up stress, not top-down.

Bottom-up stress = good

Exercise stimulates BDNF which assists with neuroplasticity and neurogenesis of hippocampal neurons, general overall tissue health, psychological resilience, independence of activities of daily living. But you need to start at a younger age so that exercise isn't viewed as more stress by the brain - body tissues have to have time and exposure to develop the capacity to handle increased blood pressure, heart rate, etc. The younger you are when you start exercising regularly the easier it will be for everything to adapt to each other, and the more adaptation capacity you will build, like creating and growing an investment portfolio.


Life of Pi, and life in a HumanAntiGravitySuit

I don't know for a fact, but it makes intuitive sense that psychological stress does us in by preventing successful automatic inhibition of spinal cord mechanisms, increasing the opportunities for those pesky little microglia to fatten up and reproduce themselves endlessly in our spinal cord ecology, maintain persisting nociceptive input at the expense of our personal comfort - "we," the "self"s, the "i"-illusions that must share a nervous system with a panicky, badly-trained, or in some cases, just plain old cranky critter brain, until death do us part.

I enjoyed Life of Pi, both the book and movie.

All of us are going to die. All of us are in the lifeboat with the tiger. We can figure out how to live with it as long as possible (successful living, barring overt disease), or we can let it kill us sooner rather than later (not learn how to overcome stress/pain). Best outcome is, it's a draw, and we both die at the same time, having become friends. Which might be the most sensible thing to do, from a stress minimization standpoint.

I'm pretty sure the only shot most of us have at successfully aging (barring overt disease), i.e., not having to put up with a lot of pain or disability associated with pain, is to learn how to create boundaries for psychological health, and manage our contexts adequately, eat properly, exercise daily for our physiological health.

Exercise can keep the hippocampus fluffier, because of bottom-up BDNF neuroplasticity; having more neurons, new baby ones, continuously, may help maintain that homeostatic capacity our brain has to manage physiological stress responses appropriately in a timely manner. Living one's own life, not other peoples', will help too.    

Previous blogposts

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall;  Part 7bGate control: "The theory was a leap of faith but it was right!"

Part 8: Beyond the gate: Self as mayor Part 8b: 3-ring circus of self Part 8c: Getting objective about subjectivity

Part 9: Phantom pain - in the brain! Part 9b: Dawn of the Neuromatrix model Part 9cNeuromatrix: MORE than just spinal projection areas in thalamus and cortex Part 9d: More about phantom body pain in paraplegics

Part 10: "We don't need a body to feel a body." Part 10b: Conclusion1: The brain generates its own experience of being in a body Part 10c:Conclusion 2: Your brain, not your body, tells you what you're feeling Part 10dConclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10eThe neural network that both comprises and moves "Self" is (only)modified by sensory experience

Part 11We need a new conceptual brain model! Part 11b: Intro to a new conceptual nervous system Part 11c: Older brain models just don't cut it Part 11d: The NEW brain model!

Part 12: Action! 12b: Examining the motor system, first pass. 12c: Motor output and nervous systems - where they EACH came from Part 12d... deeper and deeper into basal ganglia Part 12e: Still awfully deep in basal ganglia Part 12f: Surfacing out of basal ganglia Part 12gThe Action-Neuromatrix 

Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity

Part 14: Side trip out to the periphery! Part 14b: Prevention of pain neurotags is WAY easier than cure Part 14cPW Nathan was an interesting pain researcher  Part 14dBrain glia are from neuroectoderm and PNS glia are from neural crest Part 14e: The stars in our headsPart 14f: Gleeful about glia Part 14g: ERKs and MAPKs and pain Part 14h: glia-fication of nociceptive input 14i: molecular mediators large and small Part 14j: Neurons, calling glia (over, do you read?) Part 14k: Glia calling glia, over. Do you read? Part 14l: satellite cell and neuron cell body interactions, and we're outta here!

Part 15: Prevention of neurobiological hoarding behaviour by dorsal horn and DRG glia is easier than clutter-busting after the fact

Part 16: Apples are to fruit as cows are to animals as nociceptive input is to pain

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