Re: Pain-neurochem final/ thanks

July 19, 1998

, Thank you for sharing the essay. I've printed it out and am

sending a copy of it to my former neurologist, maybe he'll learn

something..Pati

--- " 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.

>

<HR>

<HTML>

<HEAD>

<TITLE>Pain-neurochem final</TITLE>

<X-SAS-WINDOW TOP=42 BOTTOM=465 LEFT=109 RIGHT=604>

</HEAD>

<H1><CENTER>The Neurochemical Basis of Pain and Analgesia

</CENTER></H1>

<CENTER><A HREF= " ../home.html "

TARGET= " window " >Dave Rakoff</A> - <FONT

SIZE= " +1 " ><A HREF= " http://www.students.haverford.edu "

TARGET= " window " >Haverford College</A></CENTER>

<CENTER><A HREF= " mailto:dprescot@... " >Dr.

Prescott</A> - Neurochemistry 322 -

<A HREF= " http://www.brynmawr.edu "

TARGET= " window " >Bryn Mawr College</A> - May

1997</CENTER>

<CENTER>Many of the links within this document

lead to <A HREF= " http://www.eb.com "

TARGET= " window " >Britannica Online</A>, and may

not be accessible from outside the Tri-Co.

</CENTER>

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:

<A

HREF= " http://rpiwww.mdacc.tmc.edu:80/se/anatomy/brain/gross_brain_left.jpg "

TARGET= " window " >brain</A> is behavior. Many aspects of sensory

behavior such as vision and hearing demonstrate that there is a gap

between <A HREF= " ../nbb/final.html " TARGET= " nbb " >perception and

reality.</A> 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

<A HREF= " /drakoff/nbb/final.html#colorvision " TARGET= " nbb " >nothing

" colorful " about a photon.</A> 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.<A NAME= " pain " ></A>

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 <A HREF= " prostasp.html "

TARGET= " prostasp " >prostaglandin</A> hormone following tissue damage.

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5009/2/188.html & DBase=Articles & \

hits=10 & context=all & pt=1 & keywords=pain#4UR06 "

TARGET= " window " >Aspirin</A>,

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=micro/3/15.html & DBase=Articles & hits=1\

0 & context=all & pt=1 & keywords=pain "

TARGET= " window " >Tylenol</A>, and

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=micro/286/9.html & DBase=Articles & hits=\

10 & context=all & pt=1 & keywords=pain "

TARGET= " window " >Ibuprofen</A> function at this level by

blocking the synthesis of prostglandin from its precursor

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5009/2/187.html & DBase=Articles & \

hits=10 & context=all & pt=1 & keywords=pain#4UQYV "

TARGET= " window " >arachidonic acid</A>. This type of

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=micro/21/67.html & DBase=Articles & hits=\

10 & context=all & pt=1 & keywords=pain "

TARGET= " window " >analgesia</A> 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

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5009/2/226.html & DBase=Articles & \

hits=10 & context=all & pt=1 & keywords=histamine#43DYP "

TARGET= " window " >histamine</A>, a chemical which is also released by

the damaged cell. (Carlson, 1994<FONT

SIZE= " -2 " >) The activated pain receptor will enter the

<A HREF= " pathway.gif " TARGET= " window " >spinal cord</A> dorsally,

synapsing immediately with neurons in the marginal zone and

substantia gelatinosa of the gray matter, releasing

<A

HREF= " http://wwv.genderm.com/genderm/arthritis/how/clinical/pharmacology/neurobi\

ology/neuro.html "

TARGET= " window " >substance P</A>. These neurons will cross to the

other side of the spinal cord and <A HREF= " pathway.gif "

TARGET= " window " >ascend</A> 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).<A NAME= " CNS " ></A>

Inhibition of pain can take place in

the CNS as well as the PNS, and indeed this is where the situation

becomes much more <A HREF= " types.html " TARGET= " types " >interesting as

well as complicated</A>. 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, <A HREF= " http://www.halcyon.com/dember/studies.html "

TARGET= " window " >acupuncture</A>, stress, cultural background, and

<A HREF= " http://www.loop.com/~bkrentzman/meds/placebo.html "

TARGET= " window " >sugar pills</A> 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 <A HREF= " http://www.csccc.com/newslett/art1296.htm "

TARGET= " window " >relief of the subjective component of pain</A> is

often desirable. Analgesia at this level is dependent upon the

modulation of neurotransmitters, which can lead to various addictions

and other adverse effects.<A NAME= " stimulation " ></A>

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 <A HREF= " PAG.gif "

TARGET= " window " >periaqueductal gray area (PAG)</A> 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 <A HREF= " bigpath.JPG " TARGET= " window " >brain's

endogenous mechanism</A> 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.<A NAME= " stress " ></A>

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.

<CENTER><IMG SRC= " morph.gif " ALT= " Morphine Strucutre " WIDTH=200

HEIGHT=200 ALIGN=right></CENTER>

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)<A NAME= " serotonin " ></A>

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 <A HREF= " neuron.gif "

TARGET= " window " >descending analgesic pathway</A> 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 (<A HREF= " #pain " TARGET= " right " >see above</A>), 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.

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5001/75/45.html & bold=on & sw=neur\

otensin & DBase=Articles & hits=10 & context=all & pt=1 & keywords=neurotensin#first_hit "

TARGET= " window " >neurotensin</A> 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

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5004/57/43.html & DBase=Articles & \

hits=10 & context=all & pt=1 & keywords=neurotensin#8HWGX "

TARGET= " window " >serotonergic</A> 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. <A NAME= " naloxone " ></A>

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.

<CENTER><IMG SRC= " naloxone.GIF " WIDTH= " 50% " HEIGHT= " 50% "

ALIGN=left></CENTER>

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

<A HREF= " http://www.halcyon.com/dember/studies.html "

TARGET= " window " >acupuncture</A> were (Mayer et al, 1976, from

Carlson).<A NAME= " nonopioid " ></A>

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

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5004/57/43.html & DBase=Articles & \

hits=10 & context=all & pt=1 & keywords=neurotensin#8HWGX "

TARGET= " window " >serotonin</A> 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

<A HREF= " #serotonin " TARGET= " right " >above</A>, 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

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5004/57/45.html & bold=on & sw=NMDA\

& DBase=Articles & hits=10 & context=all & pt=1 & keywords=NMDA#first_hit "

TARGET= " window " >NMDA</A>. 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

<A

HREF= " http://www.eb.com:180/cgi-bin/g?DocF=macro/5004/57/45.html & bold=on & sw=NMDA\

& DBase=Articles & hits=10 & context=all & pt=1 & keywords=NMDA#first_hit " >NMDA</A>

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.<A NAME= " conclusion " ></A>

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

<A HREF= " bibliog.html " TARGET= " right " >bibliography</A>, as well the

help and guidance of my professors, both at

<A HREF= " http://www.brynmawr.edu " TARGET= " window " >BMC</A> and

<A HREF= " http://www.haverford.edu " TARGET= " window " >HC</A>.

<CENTER><A HREF= " mailto:drakoff@... " >Email the

author</A> feedback or questions</CENTER>

<CENTER>This work is copyrighted by A.

Rakoff, 1997.

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