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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 saporin, 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.
Prepared by: Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD
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