Re: Pain-neurochem final-Nice try but no cigar!

[Guest guest]

Hi All,

It is very popular to offer chemical solutions to every body issue.

This is done almost universally. There are very few doctors who

specialize in electro-physiology of the body. However there has been

some brilliant work done anyway. One researcher & med electronics

designer discussses that all body cells emit alpha waves (this is

generally a healthy brain-wave). The theory goes that pain disrupts the

healthy alpha pattern, sending disrupted pain alpha wave signals to the

brain. Support for this can be found in the Alpha-Stim device, which

corrects the alpha wave pattern & can relieve pain.

Ken

E. Darwent wrote:

> http://www.students.haverford.edu/drakoff/pain/pain.html

>

> Greetings Listers: Here is an essay written for a final exam possibly. The

> topics covered deal with the Neurochemical Basis of Pain and Analgesia. From

> what I have seen it looks to be informative. You as the Reader may find it of

> interest to you.

>

> Peace

>

> D.

>

> ----------------------------------------------------------------

>

>

>

> The Neurochemical Basis of Pain and Analgesia

>

> Dave Rakoff - Haverford College

> Dr. Prescott - Neurochemistry 322 - Bryn Mawr College - May 1997

> Many of the links within this document lead to Britannica Online, and

> may not be accessible from outside the Tri-Co.

> ------------------------------------------------------------

>

> One of the central themes of neurobiology is that all of behavior -

> moods, sleeping, eating, thirsting, lusting, sensing and movement, and

> thought - arises from the activity of neurons. This implies that there

> is no mind separate from the body, and Grobstein states this

> succinctly: brain is behavior. Many aspects of sensory behavior such

> as vision and hearing demonstrate that there is a gap between

> perception and reality. This is understandable in terms of the fact

> that our nervous system only takes a sampling of stimuli in the

> physical world, and then converts the information into action

> potentials. Such fundamental behaviors as perception and sensation are

> therefore subjective.

>

> A classic example of this can be found in the neuroscientist's answer

> to the question ' If a tree falls in the forest, and nobody is around

> to hear it, does it make a sound? " It is necessary to distinguish

> between the compression and rarefaction of air as a sound wave passes

> through it from the percept hearing'. In order to hear, neurons in the

> ear must be activated, and must project the signal to the auditory

> cortex in the brain. Only then can a sound be heard. A tree that dies

> a lonely death may produce a sound wave, but no sound per se.

>

> The distinction between the physical compression of air and the

> subjective interpretation by the brain is important, in that the

> pattern is repeated throughout the nervous system and is

> characteristic of its basic structure.Pain presents a clear example of

> such a pattern. There is nothing intrinsically painful in a given

> stimuli, just as in vision, there is nothing " colorful " about a

> photon. Although there are many different types of touch sensation,

> pain is more complex than being simply an extreme form of touch. Pain

> is chemically and neurologically distinct from touch, as will be

> described.

> ------------------------------------------------------------

>

> The chemicals involved in the production of a signal that will

> interpreted as painful are well mapped. Stimulation of special

> high-threshold receptors can produce a sensation of pain, however,

> stimuli that are severe enough to activate these receptors often are

> paired with cellular damage. This implies that pain might also be

> caused by a chemical released by injured cells. Indeed, it has been

> found that many cells will rapidly synthesize a prostaglandin hormone

> following tissue damage. Aspirin, Tylenol, and Ibuprofen function at

> this level by blocking the synthesis of prostglandin from its

> precursor arachidonic acid. This type of analgesia results in a

> reduction in the actual degree of activation of the sensory neuron.

> This type of modification of pain takes place exclusively in the PNS,

> and effects sensory neurons, rather than the interneurons involved in

> the ascending pain pathways.

>

> If the prostaglandin synthesis is not blocked, then the chemical will

> act to sensitize to free nerve endings in the immediate area. These

> nerve endings, now sensitized, will bind histamine, a chemical which

> is also released by the damaged cell. (Carlson, 1994) The activated

> pain receptor will enter the spinal cord dorsally, synapsing

> immediately with neurons in the marginal zone and substantia

> gelatinosa of the gray matter, releasing substance P. These neurons

> will cross to the other side of the spinal cord and ascend through the

> spinal thalamic tract or through the spinalreticular tract to the

> ventrobasal nucleus of the thalamus. From there, projections will

> branch to the somatosensory cortex, allowing the localization of the

> pain, and also to the cingulate cortex. This second projection is

> interesting in that the cingulate cortex has been linked with emotion,

> and provides a basis for the emotional component of pain. Indeed,

> lesion studies have shown that the emotional component of pain can be

> selectively eliminated by a well-placed lesion in the thalamus or

> prefrontal cortex (Carlson, 1994).

> ------------------------------------------------------------

>

> Inhibition of pain can take place in the CNS as well as the PNS, and

> indeed this is where the situation becomes much more interesting as

> well as complicated. Fortunately, this is an area that is currently

> quite actively being researched. This implies that much is not fully

> understood; however, while the modification of pain is a complicated

> neurochemical issue, some types of analgesia have been thoroughly

> studied. While we are aware that there is much that we do not yet

> know, knowledge of this inadequacy comes as a result of what we do

> know. Pain signals in the spinal cord can be mediated by a descending

> pathway that is under neurochemical control. The system can become

> activated by various stressors or by electrical stimulation, and is

> discussed in detail below.

>

>

>

> Hypnosis, acupuncture, stress, cultural background, and sugar pills

> can all exert a profound effect on the perception of pain. Carlson

> notes a study by Beecher (1959) in which injured soldiers reported

> little pain from their wounds, and declined medication. Clearly, it is

> adaptive to not feel pain at certain times, but this begs the question

> of why we feel pain to begin with. Examining individuals with

> nociceptive disorders is instructive here.

>

> While pain shouldn't be so debilitating that it interferes with

> survival behaviors such as fighting, escaping or mating, individuals

> who are born without the ability to feel pain are prone to injuries,

> some of which are fatal. For example, the pain normally associated

> with appendicitis will not be felt by such an individual and can lead

> to serious infection and death. One woman with this congenital

> insensitivity to pain did not shift when she was seated, which is

> something that people normally do without thinking. As a result, she

> damaged her spine so badly that she eventually died from the injuries.

> (Carlson) While a complete lack of pain is obviously dangerous, the

> relief of the subjective component of pain is often desirable.

> Analgesia at this level is dependent upon the modulation of

> neurotransmitters, which can lead to various addictions and other

> adverse effects.

>

>

>

> As was indicated above, analgesia can be induced by direct stimulation

> of the nervous system. For the relief of chronic pain, an electrode

> can be implanted in the periaqueductal gray area (PAG) of the brain.

> Stimulation here and in a few other key points in the brain can act to

> produce analgesia that may last for hours. Activation of the PAG

> activates the brain's endogenous mechanism for analgesia, alluded to

> earlier and further discussed below. This descending pathway acts to

> reduce the amount of substance P that is released, thereby decreasing

> the intensity of the pain signal. Analgesia produced by direct

> stimulation of the brain is called, conveniently, stimulation-produced

> analgesia.

>

> The PAG obviously must play some role in a natural pain-inhibiting

> mechanism--it did not evolve solely for the amusement of

> neuroscientists. Such phenomena as soldiers needing less anesthesia

> during war and placebo effects indicate that there is an endogenous

> mechanism to mediate nociception. Indeed, it has been found that a

> wide variety of stimuli have analgesic effects. Analgesia that is

> induced by an external stimulus is termed stress-induced analgesia

> (SIA). Many different stimuli can lead to SIA. Experimentally,

> inescapable foot shock, cold-water swim (CWS), cervical probing, and

> centrifugal rotation,among others, have all been studied extensively

> as means to induce analgesia. (Amit and Galina,1986).As well, severe

> injury or exposure to a predator has also been shown to cause

> SIA.(Kavaliers and Colwell, 1991) Somewhat paradoxically, some of the

> same stimuli that can produce analgesia can be used in its

> measurement. For example, the hot plate test is frequently used to

> measure analgesia, but has also been shown to induce it under certain

> circumstances (Hawranko et al, 1994).

>

> ------------------------------------------------------------

>

> Many exogenous chemicals have long been known to produce analgesia.

> Opium and morphine are perhaps the best known. A was noted earlier,

> pain sensation is separate from touch sensation. The existence of

> drugs which effect the sensation of pain, but do not produce

> full-blown anesthesia and permit normal touch sensation supports this

> observation. All opioids have a characteristic peperidine ring (bold)

> and methylated nitrogen, as can been seen in the structure of

> morphine, below.

>

> In the 1970's, a series of endogenous compounds

> were found that could bind at the same receptors as morphine and other

> exogenous opiates. The class of compounds was named endorphins, a

> conjunction of 'endogenous morphine'. The endorphins include leu- and

> met-enkephalon, which are both derived from the peptide

> Pro-enkephalon; beta-endorphin, which is derived from

> Pro-opiomelanocortin; and finally, dynorphin, derived from

> Pro-dynorphin. The endorphins were the first to be discovered (,

> 1975 from Carlson) and were isolated from brain tissue. They were

> found five amino acids long Try-Gly-Gly-Phe-(Leu or Met)-OH and, when

> synthesized, acted as very strong opiates. (Pasternak, 1987)

>

> The common effects of the endorphins and opiate drugs is due to

> binding to a common set of receptors. The opiate receptor subtypes

> include mu, delta, kappa, sigma, and epsilon. The chief receptor

> involved in mediating the descending analgesic pathway is the mu

> receptor. The various receptor subtypes all play roles, however, and

> Carlson notes that delta receptor is probably involved in the

> regulation of mood, and is found primarily in the limbic system; kappa

> may be related the the sedative effects of the opiates, and can be

> found in the cerebral cortex; the functions of sigma (found in the

> hippocampus) and of epsilon( found in the basal forebrain and

> hypothalamus) are not as well understood.

>

> By binding to this receptor, an opiate can inhibit the release of

> substance P (see above), and thereby decrease the activity in the

> afferent ascending pain pathway. Opiates may also bind (preferentially

> to mu receptors) at higher levels in the brain, such as in the PAG and

> the Nucleus raphe magnus in the medulla. neurotensin is then released

> at an excitatory synapse in the nucleus raphe magnus. Interneurons

> then project down the dorsolateral column of the spinal cord and

> activate, via a serotonergic synapse with yet another interneuron,

> neurons that either act pre or postsynaptically to inhibit the release

> of substance P. (Basbaum and Fields, 1984 form Carlson). The system,

> therefore, is redundant and quite complex. Opiate binding at the

> higher and lower levels is preferential to the mu opiate receptor.

>

> ------------------------------------------------------------

>

> The key to most research into analgesia has been the use of naloxone,

> which is a competitive inhibitor of mu opiate receptors. Naloxone has

> such a high affinity for the receptor that it is able to knock an

> agonist right out of the receptor and bind in its place. Naloxone

> blocks the effects of opiates by binding without activating the

> receptor (Carlson, 1994). Moreover, its high affinity means that the

> receptor is occupied for a set period of time by the naloxone before

> it is released and the receptor has a chance to once again bind an

> opiate.

>

> Because naloxone binds specifically and competitively to mu

> receptors, it can be used to determine if analgesia is being caused by

> a substance that is dependent upon binding there also. For example, in

> analgesia that results from a placebo effect, if subjects are given

> naloxone, the analgesic effects are no longer found, indicating that

> the analgesia was mediated by an opioid (Levine, Gordon and Fields

> 1979). Returning to previous example, analgesia that resulted from

> hypnosis was not blocked by naloxone, but the analgesic effects of

> acupuncture were (Mayer et al, 1976, from Carlson).

>

> ------------------------------------------------------------

>

> Of key interest is the 1976 finding of Akil, Mayer, and Liebeskind

> that the analgesia resulting from direct stimulation of the PAG was

> partly, but not entirely blocked by naloxone. This implies that there

> is another system at work in the mediation of analgesia that is not

> dependent on opiates. Since naloxone prevents opiates from binding, if

> naloxone is administered and the analgesia remains, then there is

> necessarily a non-opioid mechanism mediating nociception in addition

> to the opioid system

>

> Further evidence of this can be seen in the 1991 study by Kavaliers

> and Colwell. Herein, analgesia was induced by exposing mice to a

> stressful stimuli- an experienced predatory cat - for varying amounts

> of time. It was found that after a brief 30 second exposure to the

> cat, mice displayed a temporary non-opioid analgesia that was not

> affected by naloxone, but was blocked by the serotonin agonist

> 8-OH-DPAT. However, after the exposure time was increased to 15

> minutes, the mice displayed a naloxone sensitive opioid-based

> analgesia. Interestingly, a significant sex-difference was found,

> where male mice showed a greater opioid response, while females showed

> a larger non-opioid serotonergic response. Analogous results were also

> found in meadow voles in 1993 by Saksida, Galea, and Kavaliers.

>

> A more common paradigm for inducing analgesia is the forced swim. It

> is favored primarily because the degree of stress can be easily

> controlled by varying water temperature and swim time, and moreover,

> the stressor is non-painful compared to other methods used. Following

> such a swim, the level of analgesia is usually measured by hot-plate

> latency. In general, it appears that shorter term stressors are likely

> to lead to non-opioid mediated analgesia, whereas stressors of a

> longer duration tend toward an opioid-mediated basis. (Amit and

> Galina, 1986) Also, Amit and Galina suggest that higher intensity

> stressors will tend to lead to opioid mediated SIA, however, several

> studies were found in conflict with these generalizations, and are

> discussed below. Much work is currently going into an exploration of

> sexual differences and to the various different neurochemical

> mechanisms other than the opioid that are involved in mediating

> nociception.

>

> Serotonin, mentioned above, has been implicated as one of several

> other neuropeptides that mediate non-opioid SIA. Serotonin can be

> depleted in an animal prior to exposure to the stressor. Reductions in

> analgesia are generally not seen following short-term stressors, but

> are seen following stressors of a longer duration. These results

> appear to be in conflict with those sited above, where

> serotinergic-based SIA was found following the brief stressor.

>

> Referring to the descending pathway discussion above, and these

> studies, it can be seen that serotonin is required by the endogenous

> descending pain-inhibition pathway. When serotonin is depleted, the

> opioid pathway cannot be fully activated, but non-opioid pathways are

> not affected. This fits with the generalizations made by Amit and

> Galina, in that serotonin depletion should block opioid mediated

> analgesia, which is found from stressors of a longer duration.

>

> However, in light of the Kavaliers studies, above, it appears that

> serotonin may be involved not only as a lower-level neurotransmitter

> in the opioid pathway, but also plays a role in a separate non-opioid

> mediated analgesic pathway. The role of serotonin in this non-opioid

> pathway is clearly different, because, as was noted, the analgesia was

> blocked by a serotonin agonist. It would seem likely that the receptor

> subtypes for serotonin are different in these two systems, and

> Saksida, Galea, and Kavaliers support this notion in their discussion.

> (Saksida et al, 1993)

>

> Other neuropeptides have been implicated in the non-opioid mediated

> analgesic pathways besides serotonin, among them vasopressin,

> dopamine, norepinephrine, GABA, and NMDA. Rats that are deficient in

> vasopressin have been shown by Bodnar to not exhibit some types of

> analgesia following CWS (cold-water swim). Moreover, analgesia induced

> by vasopressin is not blocked by naloxone, implying that it is

> mediated through a separate set of binding sites, making it

> pharmacologically distinct. Dopamine has been suggested as a possible

> modulator of SIA, as DA antagonists have been shown to increase SIA;

> however, these effects might be secondary to the overall physiological

> effects of the chemicals used to modulate the level of DA present, and

> regardless, the effects of DA on SIA were not comparatively large.

>

> A series of studies conducted in the Liebeskind laboratory have

> utilized the selective NMDA receptor antagonist MK-801 to demonstrate

> the role played by NMDA in non-opioid SIA. In 1991 Marek et al showed

> that by varying the temperature of the CWS between 15, 20 and 32

> degrees C, SIA could be varied between opioid and non-opiod mediated.

> At 15C, the SIA was found to be completely attenuated by MK-801,

> implying that the SIA in very cold water was mediated by NMDA. At 32C,

> the SIA could be blocked by naloxone, but was unaffected by MK-801,

> demonstrating that the analgesia at this temperature was mediated by

> an opioid. The SIA found at the intermediate temperature could only be

> fully blocked by administering a combination of MK-801 and naloxone.

> By concluding that the less severe stress results in the

> naloxone-sensitive opioid-mediated SIA, this study stands outside of

> the generalization made earlier by Amit and Galina, as do the results

> of several other studies, referenced by Marek et al.

>

> In another study the Liebeskind lab showed that ethanol-induced

> analgesia (EIA), which had previously been found to only be partly

> blocked by naloxone, could be fully blocked by administering a

> combination of naloxone and MK-801. Although ethanol generally acts to

> depress systems, it must be activating NMDA receptors in order for the

> EIA effects to be blocked by MK-801.

>

> The neurochemical and biopsychological underpinnings of pain and

> analgesia have been investigated and discussed. We have seen that pain

> can be caused as well as mediated by a variety of stimulus, both

> psychological and physical, and that there is an identifiable

> mechanism underlying these phenomena in the nervous system, its

> pathways and its chemicals. Pain should be understood as something

> that is perhaps unpleasant at times, but a necessary and indeed

> fascinating interaction of chemistry, biology, and psychology.

>

> -----------------------------------------------------

>

> NB While no part of this paper was copied verbatim, its creation would

> not have been possible without the information found in several key

> texts and journals, listed in the bibliography, as well the help and

> guidance of my professors, both at BMC and HC.

>

> -----------------------------------------------------

> Email the author feedback or questions

> This work is copyrighted by A. Rakoff, 1997.

> -----------------------------------------------------------------------

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