Biology 202
2003 Second Web Paper
On Serendip

In 1931, the French medical missionary Dr. Albert Schweitzer wrote, "Pain is a more terrible lord of mankind than even death itself." Today, pain has become the universal disorder, a serious and costly public health issue, and a challenge for family, friends, and health care providers who must give support to the individual suffering from the physical as well as the emotional consequences of pain (1).

Early humans related pain to evil, magic, and demons. Relief of pain was the responsibility of sorcerers, shamans, priests, and priestesses, who used herbs, rites, and ceremonies as their treatments. The Greeks and Romans were the first to advance a theory of sensation, the idea that the brain and nervous system have a role in producing the perception of pain. But it was not until the middle ages and well into the Renaissance-the 1400s and 1500s-that evidence began to accumulate in support of these theories. Leonardo da Vinci and his contemporaries came to believe that the brain was the central organ responsible for sensation. Da Vinci also developed the idea that the spinal cord transmits sensations to the brain. In the 17th and 18th centuries, the study of the body and the senses continued to be a source of wonder for the world's philosophers. In 1664, the French philosopher René Descartes described what to this day is still called a "pain pathway" (5).

What prompted me to research about the various pain pathways was my grandmother's arthritis. She has suffered for many years with severe joint pain and in the past, has been treated with corticosteroids. Currently, she is taking Celebrex, (COX-2 inhibitor) which is a relatively new drug in the family of 'superaspirins'. What impressed me was how far medical research has come in the quest to conquer pain and interfere with the 'pain pathway'. "The philosophy that you have to learn to live with pain is one that I will never understand or advocate," says Dr. W. David Leak, Chairman & CEO of Pain Net, Inc. (4) . The focus of this paper has been on the numerous avenues explored by researchers and two methods of treatment that offer promising results.

What is pain? The International Association for the Study of Pain defines it as: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (1). It is useful to distinguish between two basic types of pain, acute and chronic, as they differ greatly. (7)

Acute pain, for the most part, results from disease, inflammation, or injury to tissues. This type of pain generally comes on suddenly, for example, after trauma or surgery, and may be accompanied by anxiety or emotional distress. The cause of acute pain can usually be diagnosed and treated, and the pain is self-limiting, that is, it is confined to a given period of time and severity. In some rare instances, it can become chronic (1).

Chronic pain is widely believed to represent disease itself. It can be made much worse by environmental and psychological factors. Chronic pain persists over a longer period of time than acute pain and is resistant to most medical treatments. It can, and often does, cause severe problems for patients. There may have been an initial mishap such as a sprained back, serious infection, or there may be an ongoing cause of pain such as arthritis, cancer, ear infection, but some people suffer chronic pain in the absence of any past injury or evidence of body damage(1) . Many chronic pain conditions affect older adults. Common chronic pain complaints include headache, back pain, cancer pain, arthritis pain, neurogenic pain (pain resulting from damage to the peripheral nerves or to the central nervous system itself) and psychogenic pain (pain not due to past disease or injury or any visible sign of damage inside or outside the nervous system) . (2)

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 (5).

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 (10). 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 (8).

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 . (1)

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(1) .
T
he 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 such work could be translated clinically, humans might be able to benefit from similar compounds introduced, for example, through lumbar (spinal) puncture (2).

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 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 (8).

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 (nonsteroidal anti-inflammatory drugs), act against such hormones by acting on the blood vessels. 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 (8).

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 (5).

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 (1).

Medications, acupuncture, local electrical stimulation, and brain stimulation, as well as surgery, are some treatments for chronic pain. Some physicians use placebos, which in some cases has resulted in a lessening or elimination of pain. Psychotherapy, relaxation and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain (3). Some of the latest developments include COX-2 inhibitors and chemonucleolysis (7).

COX-2 inhibitors, ("superaspirins") are thought to be particularly effective for individuals with arthritis. For many years scientists have wanted to develop the ultimate drug-a drug that works as well as morphine but without its negative side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) work by blocking two enzymes, cyclooxygenase-1 and cyclooxygenase-2, both of which promote production of hormones called prostaglandins, which in turn cause inflammation, fever, and pain. Newer drugs, called COX-2 inhibitors, primarily block cyclooxygenase-2 and are less likely to have the gastrointestinal side effects sometimes produced by NSAIDs. In 1999, the Food and Drug Administration approved two COX-2 inhibitors- rofecoxib (Vioxx) and celecoxib (Celebrex). Although the long-term effects of COX-2 inhibitors are still being evaluated, they appear to be safe. In addition, patients may be able to take COX-2 inhibitors in larger doses than aspirin and other drugs that have irritating side effects, earning them the nickname "superaspirins. (7)

Chemonucleolysis is a treatment in which an enzyme, chymopapain, is injected directly into a herniated lumbar disc in an effort to dissolve material around the disc, thus reducing pressure and pain. The procedure's use is extremely limited, in part because some patients may have a life-threatening allergic reaction to chymopapain. (3)

Thus, we see that over the centuries, science has provided us with a remarkable ability to understand and control pain with medications, surgery, and other treatments. (3) Today, scientists understand a great deal about the causes and mechanisms of pain, and research has produced dramatic improvements in the diagnosis and treatment of a number of painful disorders. (9) For people who fight every day against the limitations imposed by pain, the work of scientists holds the promise of an even greater understanding of pain in the coming years. Their research offers a powerful weapon in the battle to prolong and improve the lives of people with pain: hope (1) .

References

1)National Institute of Neurological Disorders and Stroke
2)American Pain Society
3)American Academy of Pain Management
4)PainNet.Inc
5)International Association for the Study of Pain
6)MayDay Pain Project, The.
7)Pain Treatment: Janssen-Cilag Pharm.
8)American Chronic Pain Organization
9)Rest Ministries Chronic Illness
10)Worldwide Congress on Pain


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