The paper, Pain
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Part 14: Side trip out to the periphery!
SEE ALL PREVIOUS BLOGPOSTS IN THIS SERIES LISTED AT THE END
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Yesterday we left off at reference 32, which is pretty straightforward [is what it says it is], and 33:
33. , , , Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993, 52: 259–285.
.... a 27 page review paper from 1993. In it I saw many interesting tidbits from the long (sad) history of poking or burning or otherwise bothering afferent skin nerves to try to learn more about the nervous system's pain response. Here are a few.
From the section, Clinical and experimental evidence that CNS plasticity contributes to pathological pain....
About secondary hyperalgesia, central sensitization, etc.
So, it seems that as long ago as 1950, JD Hardy, HG Wolff, and H Goodell published an oft-cited paper, Experimental evidence on the nature of cutaneous hyperalgesia (full text pdf), in which they were already differentiating various kinds of hyperalgesia, long before Cliff Woolf came along in this era (Wikipedia entry).
(Here is his most recent review paper on the topic, 37 pages, open access.)
LaMotte et al 1991 (full pdf), working with capsaicin, figured out that there was a connection between peripheral block and prevention of concomitant central changes.
Coderre et al (1991) explain:
"Recent evidence supports the view that hyperalgesia depends, in part, on central sensitization. Hyperalgesia to punctate mechanical stimuli, which develops after intradermal injection of capsaicin, is maintained even after anesthetizing the region where capsaicin was injected (LaMotte et al. 1991). However, if the skin region is anesthetized prior to capsaicin injection, cutaneous hyperalgesia does not develop. Furthermore, hyperalgesic responses to capsaicin can be prevented if the area of skin where the injection is made is rendered anesthetic by a proximal anesthetic block of the peripheral nerve which innervates it. Thus, for hyperalgesia to develop it is critical that initial inputs from the injury reach the CNS. However, once hyperalgesia is established, it does not need to be maintained by inputs from the injured peripheral tissue."-p.260
My bolds.
Makes sense. If you stop the peripheral afferent neurons being able to talk to the spinal cord in the first place, the spinal cord (which can be such a megaphone) won't relay anything because there won't be any signalling to relay. But if signalling is allowed, oops, you can end up with a red wine stain on the white sofa that will never completely come out no matter how fast you get the club soda on there. So, put those peripheral nerves to sleep proximally from where you intend to annoy them.
I was struck by a 2010 paper I found just a few months ago, by Beggs and Salter, Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier (full text pdf). It turns out the blood-spinal cord barrier is opened too. It requires action potentials to initiate this, and it's a delayed reaction, takes a couple days... but then, open sesame, the barriers open! [but for whatever reason, not in the frontal cortex and cerebellum]. The barriers become more permeable, let through much larger molecules of this and that, then go back to normal a week later. (We hope...)
What controls the blood brain and blood spinal cord barrier? Glia.
What is else is from the same neural crest origin as barrier-maintaining glia? Sensory and autonomic neurons, and Schwann cells.
Might there be some sort of sophisticated chemo-signalling system, some sort of language they speak to each other, in which specific kinds, let's say, of C-fibres, say specific things to glia, and glia respond in specific ways? I wonder. This paper doesn't speculate on any of that, but I like to.
More tidbits from Coderre et al 1991
- "Lewis (1942) showed that referred pain and hyperalgesia in the shoulder can be elicited by stimulation of the diaphragm." (The way I learned it, a) it's usually the right shoulder, and b) anything touching the diaphragm can refer there; if the left shoulder hurts persistently, spleen should be ruled out.)
- "pain of cardiac origin is referred to sites as distant as the patient’s ear (Brylin and Hindfelt 1984)"
- "referred pain has often been found to spread specifically to sites of a previous injury. Henry and Montuschi (1978) describe a case where the pain of an angina attack was referred to the site of an old vertebral fracture."
- "during high-altitude flights .. many of their patients [complained] of pain localized to teeth which had been the site of previous painful stimulation (e.g., fillings, caries and extractions), in many cases years earlier (Hutchins and Reynolds (1947)" p. 260-261
Ooh, the spidey-senses to do with neural crest tingled hard when I read that. [Talk about confirmation bias! Yes, I have a terminal case of it probably..] Neural crest makes not only sensory neurons and glia, but teeth too.
There follows a big long section on central sensitization, p 261...
"increased spontaneous activity, reduced thresholds or increased responsivity to afferent inputs, prolonged afterdischarges to repeated stimulation, and the expansion of the peripheral receptive field of dorsal horn neurons."
but also
"expansion of receptive fields of cells in the ventrobasal thalamus (Guilbaud et al. 1986)." p 262
[I will spare you all the gory details about all the many kinds of noxious provocation that went on, to rats most likely, in many labs, to measure all that over and over. And over... ]
Phantom pain
Then, a nice long section on phantom limb pain, Melzack's favorite topic I think, p262. The phenomena of feeling bunions etc in the phantom limb, and phantom limb positions that previously immobilized limbs were confined in.. all the non-limb phantom bits including organs, e.g., menstrual cramps felt post-total-hysterectomy.. pain in a phantom cornea after eye removal..
Then, a nice long section about the possibility that disinhibition might be a contributing factor.
"The interruption of afferent input associated with deafferentation may facilitate the central neural changes that contribute to the formation of pain memories by removing normal inhibitory control mechanisms.. In addition, since amputation also results in the loss of visual and tactile information related to the limb, the central influences that normally inhibit the established pain ‘traces’ may be reduced further by the absence of information from external sources that could confirm or disconfirm the percept arising from the peripheral injury." p 263
Wow, people have got to be careful with their stumps.
"Leriche (1947a,b) described a patient who did not experience phantom limb pain until 6 years after amputation, when an injection into the stump instantly, and permanently, revived the pain of a former painful ulceration of the Achilles tendon." p. 262
No inhibiting input available to the brain! And it sounds like the brain doesn't have a clue about how much time might have elapsed meanwhile. Sounds like it lives in the eternal "now."
Deafferentation pain in animals
In a section titled "Deafferentation pain in animals" (p 263) a behaviour called "autonomy" is described. Sounds benign, but this is where animals are so distressed by their deafferentated paws, or whatever, that the poor babies bite them right off. Yikes. (Sorry, this paper disturbed my empathy neurotags quite a bit. I long for the day when none of this sort of research will be necessary anymore.)
Here is another tidbit:
" ..in human amputees the incidence of phantom limb pain at 7 days and 6 months after amputation is significantly greater in patients whose pain is not treated by epidural block with bupivacaine and morphine prior to amputation surgery (Bach et al. 1988)." p 263
"Autonomy" is reduced when the nerves that are being cut are anesthetized first. Gee whiz, how about that.
"pretreatment with analgesics, but not a placebo, lessens pain and decreases postoperative analgesic requirements at a time when the agents are no longer clinically active indicates that the central component of postoperative pain can be prevented or preempted." p 266
"that the incidence of phantom limb pain is reduced if patients are rendered pain-free by epidural blockade with bupivacaine and morphine prior to amputation (Bach et al. 1988), suggests that the development of neuropathic pain can be prevented by reducing the potential for central sensitization at the time of amputation." p 276
There is a very long part to do with cellular molecular signalling which is carefully presented from all sides, and argued, which I'm sure is fascinating detail for anesthetists etc., but which made my own eyes glaze over.. Anyway, in a nutshell, this paper argues that if local block anesthetic were provided along with central, then post-op chronic pain of various kinds, including phantom limb (organ, breast, tooth, whatever) pain, could be prevented way better.
If this is true, why does a [mostly post-op] chronic pain epidemic even exist? Isn't this (old by now) information making its way into ORs? I get that there is conflicting info - this paper very carefully goes through lots of it, but why wouldn't anesthesiologists/anesthetists/surgeons go set up their own outcome trials to answer the question/ convince themselves one way or the other?
........
Back to Melzack and Katz
Anyway, we move on. Next paragraph in the "Denervation Hypersensitivity and Neuronal Hyperactivity" section of Melzack & Katz:
"Clinical neurosurgery studies reveal a similar relationship between denervation and CNS hyperactivity. Neurons in the somatosensory thalamus of patients with neuropathic pain display high spontaneous firing rates, abnormal bursting activity, and evoked responses to stimulation of body areas that normally do not activate these neurons.34,35 The site of abnormality in thalamic function appears to be somatotopically related to the painful region. In patients with complete spinal cord transection and dysesthesias referred below the level of the break, neuronal hyperactivity was observed in thalamic regions that had lost their normal sensory input, but not in regions with apparently normal afferent input.34 Furthermore, in patients with neuropathic pain, electrical stimulation of subthalamic, thalamic and capsular regions may evoke pain36 and in some instances even reproduce the patient's pain.37–39 Direct electrical stimulation of spontaneously hyperactive cells evokes pain in some but not all pain patients, raising the possibility that in certain patients the observed changes in neuronal activity may contribute to the perception of pain.34Studies of patients undergoing electrical brain stimulation during brain surgery reveal that pain is rarely elicited by test stimuli unless the patient suffers from a chronic pain problem. However, brain stimulation can elicit pain responses in patients with chronic pain that does not involve extensive nerve injury or deafferentation. Lenz et al.38 described the case of a woman with unstable angina who, during electrical stimulation of the thalamus, reported ‘heart pain like what I took nitroglycerin for’ except that ‘it starts and stops suddenly’ (p. 121). The possibility that the patient's angina was due to myocardial strain, and not the activation of a somatosensory pain memory, was ruled out by demonstrating that EKG, blood pressure, and cardiac enzymes remained unchanged over the course of stimulation."
More references to check out.
, , , , , , Abnormal single-unit activity recorded in the somatosensory thalamus of a quadriplegic patient with central pain. Pain 1987, 31:225–236.
35. , , , Characteristics of the bursting pattern of action potential that occurs in the thalamus of patients with central pain. Brain Res 1989, 496:357–360.
36. Stereotactic surgery. In: , , eds. Textbook of Pain. Edinburgh: Churchill Livingstone; 1989, 840–855.
Pain and nociception in the clinical context. Phil Trans Royal Soc Lond 1985, 308:219–226.
38. , , , , , , The sensation of angina can be evoked by stimulation of the human thalamus. Pain 1994, 59:119–125.
39. , , , , Visceral pain evoked by thalamic microstimulation in humans.Neuroreport 1995, 6:369–374.
At this rate, we'll make [s...l...o...w...] progress, but we'll be stuck in fog for a long time. So, the scenery will continue to be not very exciting I'm afraid.
...............
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 11: We 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 11: We 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!
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