Chronic Pain (cont.)
A pain primer: what do we know about pain?
We may experience pain as a prick,
tingle, sting, burn, or ache. Receptors on the skin trigger a series of events,
beginning with an electrical impulse that travels from the skin to the spinal
cord. The spinal cord acts as a sort of relay center where the pain signal can
be blocked, enhanced, or otherwise modified before it is relayed to the brain.
One area of the spinal cord in particular, called the dorsal horn, is important in the reception of pain signals.
The most common destination in the brain for pain
signals is the thalamus and from there to the cortex, the headquarters for
complex thoughts. The thalamus also serves as the brain's storage area for
images of the body and plays a key role in relaying messages between the brain
and various parts of the body. In people who undergo an amputation, the
representation of the amputated limb is stored in the thalamus. (For a
discussion of the thalamus and its role in this phenomenon, called phantom pain,
see section on Phantom Pain in the Appendix.)
Pain is a complicated process that involves an intricate interplay between a
number of important chemicals found naturally in the brain and spinal cord. In
general, these chemicals, called neurotransmitters, transmit nerve impulses from
one cell to another.
There are many different neurotransmitters in the human body; some play a
role in human disease and, in the case of pain, act in various combinations to
produce painful sensations in the body. Some chemicals govern mild pain
sensations; others control intense or severe pain.
The body's chemicals act in the transmission of pain messages by stimulating
neurotransmitter receptors found on the surface of cells; each receptor has a
corresponding neurotransmitter. Receptors function much like gates or ports and
enable pain messages to pass through and on to neighboring cells. One brain
chemical of special interest to neuroscientists is glutamate. During
experiments, mice with blocked glutamate receptors show a reduction in their
responses to pain. Other important receptors in pain transmission are
opiate-like receptors. Morphine and other opioid drugs work by locking on to
these opioid receptors, switching on pain-inhibiting pathways or circuits, and
thereby blocking pain.
Another type of receptor that responds to painful stimuli is called a
nociceptor. Nociceptors are thin nerve fibers in the skin, muscle, and other
body tissues, that, when stimulated, carry pain signals to the spinal cord and
brain. Normally, nociceptors only respond to strong stimuli such as a pinch.
However, when tissues become injured or inflamed, as with a sunburn or
infection, they release chemicals that make nociceptors much more sensitive and
cause them to transmit pain signals in response to even gentle stimuli such as
breeze or a caress. This condition is called allodynia -a state in which pain is
produced by innocuous stimuli.
The body's natural painkillers may yet prove to be the most promising pain
relievers, pointing to one of the most important new avenues in drug
development. The brain may signal the release of painkillers found in the spinal
cord, including serotonin, norepinephrine, and opioid-like chemicals. Many
pharmaceutical companies are working to synthesize these substances in
laboratories as future medications.
Endorphins and enkephalins are other natural painkillers. Endorphins may be
responsible for the "feel good" effects experienced by many people
after rigorous exercise; they are also implicated in the pleasurable effects of
smoking.
Similarly, peptides, compounds that make up proteins in
the body, play a role in pain responses. Mice bred experimentally to lack a gene
for two peptides
called tachykinins-neurokinin A and substance P-have a reduced response to
severe pain. When exposed to mild pain, these mice react in the same way as mice
that carry the missing gene. But when exposed to more severe pain, the mice
exhibit a reduced pain response. This suggests that the two peptides are
involved in the production of pain sensations, especially moderate-to-severe
pain. Continued research on tachykinins, conducted with support from the NINDS,
may pave the way for drugs tailored to treat different severities of pain.
Scientists are working to develop potent pain-killing drugs that act on
receptors for the chemical acetylcholine. For example, a type of frog native to
Ecuador has been found to have a chemical in its skin called epibatidine,
derived from the frog's scientific name, Epipedobates tricolor. Although highly
toxic, epibatidine is a potent analgesic and, surprisingly, resembles the
chemical nicotine found in cigarettes. Also under development are other less
toxic compounds that act on acetylcholine receptors and may prove to be more
potent than morphine but without its addictive properties.
The idea of using receptors as gateways for pain drugs
is a novel idea, supported by experiments involving substance P. Investigators
have been able to isolate a tiny population of neurons, located in the spinal
cord, that together form a major portion of the pathway responsible for carrying
persistent pain signals to the brain. When animals were given injections of a
lethal cocktail containing substance P linked to the chemical sophorin, this
group of cells, whose sole function is to communicate pain, were killed.
Receptors for substance P served as a portal or point of entry for the compound.
Within days of the injections, the targeted neurons, located in the outer layer
of the spinal cord along its entire length, absorbed the compound and were
neutralized. The animals' behavior was completely normal; they no longer
exhibited signs of pain following injury or had an exaggerated pain response.
Importantly, the animals still responded to acute, that is, normal, pain. This
is a critical finding as it is important to retain the body's ability to detect
potentially injurious stimuli. The protective, early warning signal that pain
provides is essential
for normal functioning. If this work can be translated clinically, humans might
be able to benefit from similar compounds introduced, for example, through
lumbar (spinal) puncture.
Another promising area of research using the body's
natural pain-killing abilities is the transplantation of chromaffin cells into
the spinal cords of animals bred experimentally to develop arthritis. Chromaffin
cells produce several of the body's pain-killing substances and are part of the
adrenal medulla, which sits on top of the kidney. Within a week or so, rats receiving
these transplants cease to exhibit telltale signs of pain. Scientists, working
with support from the NINDS, believe the transplants help the animals recover
from pain-related cellular damage. Extensive animal studies will be required to
learn if this technique might be of value to humans with severe pain.
One way to control pain outside of the brain, that is,
peripherally, is by inhibiting hormones called prostaglandins. Prostaglandins
stimulate nerves at the site of injury and cause inflammation and fever. Certain
drugs, including NSAIDs, act against such hormones by blocking the enzyme that
is required for their synthesis.
Blood vessel walls stretch or dilate during a migraine attack and it is
thought that serotonin plays a complicated role in this process. For example,
before a migraine headache, serotonin levels fall. Drugs for migraine include
the triptans: sumatriptan (Imitrix), naratriptan (Amerge), and zolmitriptan
(Zomig). They are called serotonin agonists because they mimic the action of
endogenous (natural) serotonin and bind to specific subtypes of serotonin
receptors.
Ongoing pain research, much of it supported by the
NINDS, continues to reveal at an unprecedented pace fascinating insights into
how genetics, the immune
system, and the skin contribute to pain responses.
The explosion of knowledge about human genetics is
helping scientists who work in the field of drug development. We know, for
example, that the pain-killing properties of codeine rely heavily on a liver
enzyme, CYP2D6, which
helps convert codeine into morphine. A small number of people genetically lack
the enzyme CYP2D6; when given codeine, these individuals do not get pain relief.
CYP2D6 also helps break down certain other drugs. People who genetically lack
CYP2D6 may not be able to cleanse their systems of these drugs and may be
vulnerable to drug toxicity. CYP2D6 is currently under investigation for its
role in pain.
In his research, the late John C. Liebeskind, a renowned
pain expert and a professor of psychology at UCLA, found that pain can kill by
delaying healing and causing cancer to spread. In his pioneering research on the
immune system
and pain, Dr. Liebeskind studied the effects of stress-such as surgery-on the
immune system and in particular on cells called natural killer or NK cells.
These cells are thought to help protect the body against tumors. In one study
conducted with rats, Dr. Liebeskind found that, following experimental surgery,
NK cell activity was suppressed, causing the cancer to spread more rapidly. When
the animals were treated with morphine, however, they were able to avoid this
reaction to stress.
The link between the nervous and immune systems is an important one.
Cytokines, a type of protein found in the nervous system, are also part of the
body's immune system, the body's shield for fighting off disease. Cytokines can
trigger pain by promoting inflammation, even in the absence of injury or damage.
Certain types of cytokines have been linked to nervous system injury. After
trauma, cytokine levels rise in the brain and spinal cord and at the site in the
peripheral nervous system where the injury occurred. Improvements in our
understanding of the precise role of cytokines in producing pain, especially
pain resulting from injury, may lead to new classes of drugs that can block the
action of these substances.
Next: What is the future of pain research? »
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