Part 17: The stress of it all Part 17b: Stress and adrenals Part 17c: Women, pain, and stress Part 17d: Stress, aging, and pain Part 17e: Stress and aging, keeping hippocampal dendrites fluffed up Part 17f: Chrousos and Gold and stress Part 17g: Stress conceptualization through the ages
SEE ALL PREVIOUS BLOGPOSTS IN THIS SERIES LISTED AT THE END
So here we are, on yet another side trip away from Melzack and Katz, sailing along on a fair day on a lovely broad stretch of side river, working our way through Chrousos and Gold 1992, learning all about stress from a couple of the world's leading researchers on the topic - maybe in the process we'll uncover clues as to why M & K like this particular paper so much.
Phenomenology of stress
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In the section titled "Stress Syndrome: Phenomenology" the authors describe a normal, adaptive stress response:
"Both physical and emotional Stressors set into motion central and peripheral responses designed to preserve homeostasis. Centrally, there is a facilitation of neural pathways mediating, among other functions, arousal, alertness, vigilance, cognition, and focused attention, as well as appropriate aggression, with concurrent inhibition of pathways that subserve vegetative functions, such as feeding and reproduction. Peripheral changes occur principally to promote an adaptive redirection of energy. Thus, oxygen and nutrients are directed to the central nervous system and the stressed body site(s). Moreover, increases in cardiovascular tone lead to elevations in blood pressure and heart rate, while increases in respiratory rate, gluconeogenesis, and lipolysis all promote enhanced availability of vital substrates. As a corollary, peripherally mediated restraint of growth and reproduction preserves energy that could be used more efficiently to the adaptive advantage conferred by a successful general adaptational response. The latter depends not only on its capacity to respond quickly to appropriate stimuli, but also on its ability to respond to counterregulatory elements that prevent an overresponse. Hence, every element of the stress response, including that originating from an inflammatory/immunereaction, must briskly respond to restraining forces. Otherwise, these responses lose their adaptive quality and contribute to the process of pathological change."
I think the take-home point might be the one I bolded.
Yeah.. I think if I had a nociceptive situation going on that was becoming less and less well regulated, because of normal aging with my hippocampus fraying and its dendrites disappearing because of my being a couch potato most of my adult life, and the microglia and maybe other glia in my spinal cord had become numerous and well-fed, and spewed their molecules everywhere like seagulls do droppings, That might turn into a bit of a situation after awhile. I can see that..
"Otherwise, these responses lose their adaptive quality and contribute to the process of pathological change."
Hmm..
Uh-oh.
Physiology of stress
Chrousos and Gold go on to mention the "informational substances" released by discrete bits of brain under stress, corticotropin-releasing hormone (CRH), by widespread bits of brain but mainly by the paraventricular nucleus of the hypothalamus, and norepinephine released by locus ceruleus (LC-NE). They point out that this discrete, dedicated system evolved specifically to manage adaptation to stress and that general adaptation response is essential to survival. They cover the pituitary adrenal axis response, sympathetic nervous system response. They say,
"CRH in moderate doses enhances arousal and promotes cautious restraint, while inhibiting vegetative functions such as feeding and reproduction. In larger doses, the central administration of CRH produces effects that can be construed as frankly anxiogenic, including hyper-responsiveness to sensory stimuli, assumption of the freeze posture and decreased exploration in unfamiliar environments, and enhancement of conditioned fear responses during aversive stimuli."
Aha. Too much makes for a jumpy organism who doesn't like to move around as much. Hmmn..
About the LC-NE response:
"The LC-NE/sympathetic systems are located in the brain stem. Activation of the LC-NE system leads to release of NE from an extraordinarily dense network of neurons throughout the brain, resulting in enhanced arousal and vigilance, as well as increased anxiety. Classically, the sympathetic division of the autonomic system is primarily associated with conferring an adaptive advantage during stressful situations via its effectors, the sympathetic nerves and the adrenal medulla, located in the periphery. The parasympathetic division of the autonomic nervous system, on the other hand, is closely linked functionally to the sympathetic system. Primarily, however, it produces effects antithetical to those of the sympathetic nervous system, whereas its inhibition can produce effects analogous to those of sympathetic activation. Although, to maintain simplicity, we refer herein to the sympathetic system only, one should keep in mind the concurrent stress-related changes of its parasympathetic counterpart."
Good point: watch out for the parasympathetic system. If it's inhibited, it might seem like too much sympathetic response is going on. So something that looks the same from the outside might not be a sympathetic nervous system being overactive, but rather a parasympathetic nervous system that is under-active.
Have you ever been in the middle of treating somebody in a slow, kind, non-nociceptive way and their digestive system suddenly begins to rumble and gurgle? I think that means the parasympathetic nervous system has activated.
Next they describe all the ways the two systems interact. They include this lovely visual synopsis and describe each detail. I'll do my best:
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1. Reciprocal innervation: Fibres from "CRH-secreting neurons from the lateral paraventricular nucleus (PVN)" of the hypothalamus project all the way to the "arousal and sympathetic systems in the hindbrain," and "projections of catecholaminergic fibers from the LC-NE system, via the ascending noradrenergic bundle, to the PVN" in the hypothalamus. Thus do CRH and LC-NE "seem to participate in a positive reverberatory feedback loop" activating each other. (Like two nine-year-old children who have been allowed to sleep outside in a tent in the yard, scaring each other with ghost stories...)
2. Similar response to secreted neurochemicals: Various neurochemical modulators affect them similarly, e.g., serotonin and acetylcholine excite both systems, while gabaergic, opioid peptidergic, and glucocorticoids inhibit them.
3. Relationship to arcuate nucleus: Neurons there supply pro-opio-melano-cortin. CRH fibres project there, facilitating release of corticotropin and beta endorphin, both of which provide negative feedback to more release of CRH from PVN. (So that's good.. maybe...)
4. Neurochemical feedback: Both systems "respond to autoregulation by CHR and alpha2-adrenergic-mediated inhibition, respectively."
5. Arginine vasopressin: "synergizes CRH's capacity to release corticotropin and beta endorphin from anterior pituitary and hypothalamus, stimulates LC-NE, might synergistically enhance some of the central behavioural effects of CRH as well."
6. Dynorphins: CRH stimulates dynorphin release and dynorphin inhibits CRH release. Dynorphin 17 significantly inhibits the activating actions of CRH on the LC-NE/sympathetic systems.
But there is more, so much more to this:
"The stress system that plays so profound a role in setting the level of arousal also interacts with other central nervous system elements that influence the retrievability and analysis of information, the initiation of specific action, and the setting of the emotional tone." - p 1246
Chrousos and Gold describe other brain systems affected by stress response (as many as they knew about 21 years ago, at least..)
"Three major brain systems are activated by the stress system and, in turn, influence its activity."
1. Mesocortical and mesolimbic dopamine systems: These are activated by LC-NE stress response. Mesocortical innervates prefrontal cortex (anticipatory phenomena, cognitive function). Mesolimbic innervates nucleus accumbens (motivation, reinforcement, reward).
2. Amygdala/hippocampus: This is directly activated by noradrenergic neurons from the LC-NE system, and also by "incoming "emotional" Stressor, such as conditioned fear, generated, perhaps, at memory-storing subcortical and cortical fields." - p 1246 The amygdala has to sort out fast what kind of stressor it is - it has to retrieve information and conduct emotional analysis. The hippocampus acts to inhibit the amygdala and the PNV-CRH system. (... like a grumpy old guy of the brain, who thinks he's seen it all and done it all, yelling, get off my lawn, you kids! ... arrrarrrrararrr... not this again dag-nabit..!)
3. Arcuate nucleus: We already discussed this one, see above. In this section Chrousos and Gold say arcuate proopiomelanocortin neurons project to PVN and other brain areas and brainstem areas to counterregulate stress response. They induce opioid-receptor-mediated activity/stress-related analgesia, maybe influence emotional tone by a bit or a lot.
Yet more effects on the organism's brain:
1. Reproductive axis: inhibited at all levels by stress response
directly and via beta endorphin, CRH "suppresses the luteinizing hormone-releasing hormone neuron of the arcuate nucleus of the hypothalamus." "Glucocorticoids.. exert inhibitory effects at the levels of the luteinizing hormone releasing hormone neuron, the pituitary gonadotroph, and the gonad itself and render target tissues of sex steroids resistant to these hormones." (Good grief.)
2. Growth axis: Growth hormone might elevate briefly at the onset of a stress response, but prolonged activation suppresses it. Apparently CRH stimulates somatostatin secretion. Growth hormone secretion is thereby inhibited - "acutely stimulatory but chronically inhibitory." Thyroid stimulating hormone is also affected, thyroid axis inhibited.
"Stress is associated with decreased production of thyroid-stimulating hormone and inhibition of conversion of the relatively inactive thyroxine to the more biologically active triiodothyronine in peripheral tissues." - p 1247
Exact mechanisms weren't known in 1992 (maybe they are now) and Chrousos and Gold speculate that perhaps this has to do with conservation of energy during a stressful time.
3. Inflammatory/immune system: profound inhibitory effects. Glucocorticoids suppress leukocyte traffic and function, and decrease production of cytokines and other mediators of inflammation.
"Conversely, however, several products of the immune system exert stimulatory effects on the axis, hence closing a negative feedback loop. Most stimulatory effects from the immune system are exerted by the inflammatory cytokines interleukin 1 (IL-1), IL-6, and tumor necrosis factor, or by mediators of inflammation—such as several eicosanoids and platelet-activating factor— on hypothalamic CRH secretion. It is not clear which of the above effects are endocrine and which paracrine. Presence of cytokinergic neural pathways and local involvement of eicosanoids and platelet-activating factor in CRH secretion are certain. Direct effects of cytokines and mediators of inflammation on pituitary corticotropin secretion, on the other hand, have also been shown or suggested for IL-1, IL-6, tumor necrosis factor, serotonin, several eicosanoids, and platelet-activating factor, and direct effects on adrenal glucocorticoid secretion might also be present." - p. 1247
So, sounds like an exciting bit is coming up next - what happens if one or the other starts winning instead of being kept in check by the other?
Next, Chrousos and Gold discuss pathophysiology in the stress system.
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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 7b: Gate 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 9c: Neuromatrix: 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 10d: Conclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10e: The neural network that both comprises and moves "Self" is (only)modified by sensory experience
Part 7: Gate control theory has stood the test of time: Patrick David Wall; Part 7b: Gate 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 9c: Neuromatrix: 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 10d: Conclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10e: The neural network that both comprises and moves "Self" is (only)modified by sensory experience
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