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Biology 202
2000 First Web Report
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It's chronic: Pain and Its Pharmacology

Laura Chivers

We all have experienced a pain that we would call excruciating. It may be a stubbed toe for some, or wisdom teeth extraction for others. In any case, we have all experienced "the worst pain of our lives." However, in this statement is the implicit idea that we no longer experience this "worst pain." The pain subsides and we eventually experience relief. This is acute pain.

Chronic pain is very different from acute pain. Although it may start with an injury that causes pain, sometimes it does not. And unlike acute pain, it persists. In chronic pain, pain signals relentlessly fire in the nervous system, perhaps continuing for years. This is the sort of pain that Emily Dickinson had in mind when she wrote this poem:

Pain has an element of blank:
It cannot recollect
When it began or if there were
A time when it was not.

What causes this unrelenting pain with an "element of blank"? To understand this, we must first understand the mechanisms of pain.

Pain that is caused by a stimulus seems to be due to the reception of pain by nocioreceptors. These nocioreceptors are nerve fibers in the body that only send signals to the brain when they receive strong stimulation (2). Some of these receptors fire in response to various painful stimuli, others are more selective (1). Damage to these nocioreceptor neurons alter the way that they can respond to noradrenaline and makes them more sensitive after injury, which may be the cause of some types of chronic pain (1). . Damage also cases the cells to release chemical mediators of pain and inflammation, including potassium ions, bradykinin, prostaglandins, serotonin, and histamine (3), as well as substance P (4).

Once these nocioreceptors receive the signal, they send it to the spinal cord, which may send out a signal for a response. The signal also continues up the spinal cord to the medulla, then the thalamus, and then to the cerebral cortex, where pain is perceived. This message of pain appears to get to the brain only by passing through a series of gates. According to the gate theory of pain (Melzack and Hall, 1965), signals in the neurosystem excite a group of small neurons that form a kind of "pain pool." When the threshold of these neurons is reached, a hypothetical gate opens and allows the signals to be sent higher. However, nearby neurons could suppress the neurons, so that the gate stays closed and the signal travels no further. This closing could be caused by the stimulation through nearby larger neurons, which respond to non-painful touch or pressure (explains why sucking a wounded thumb or rubbing a sprained ankle makes it "feel better"). The neurons could also be inhibited by activation in the descending pathway, which could activate inhibitors such as serotonin or opiod peptides (endorphins, enkephalins) (2), (3). Such inhibitors are released by the brain, bind to receptors on cells in the brain or spinal cord, and inhibit the action of these cells. Continuing pain eventually rewires this entire system so that it becomes even more sensitive to pain (2).

Another chemical that nocioreceptors use to communicate messages of pain is substance P. A chemical called capsacin, found in green peppers, stimulates nerves in a way that exhausts substance P and thus helps to relieve pain(2). Another treatment involves combining substance P with saporin (SAP), a ribosome-inactivating protein. When administered before or after the development of neuropathic pain, P-SAP will inhibit the pain associated with nerve injury, as well as significantly reduce sensitivity to stimuli associated with inflammatory pain (5).

Another treatment, and one which is very familiar, is the treatment of chronic pain with opiate compounds such as morphine or Demerol. Chronic pain patients have been found to have a lower-than-normal level of endorphins in their spinal fluid, suggesting that their bodies do not properly inhibit pain themselves (1). Opiates bind with the body's natural opiod receptors and activate them like the natural endorphins, which inhibit the "pain pool" neurons. Although very effective, these drugs also affect other systems and may cause side effects such as constipation and respiratory depression. These drugs also so have a high propensity for addiction.

Another possible treatment at the level of the opiod receptors is to inject natural endorphins into the spinal cord. Like the endorphins already present in the body, the introduced endorphins should inhibit the opening of the gate and therefore inhibit pain. The problem with this treatment is that endorphins are difficult to administer, needing to be injected into the spinal cord or brain in the right place and in quantity(2). However, endorphins are up to ten times more effective than morphine in treating pain, so such a treatment would be very beneficial.

A new treatment is offering new hope to many patients that benefit neither from analgesics nor from opiates to treat their pain. Venom from a poisonous snail (Conus sea snail) has been found effective in treating neuropathic pain that results from a malfunction in the nervous system set off by nerve damage (4) is able to block the entryways that calcium uses to cause the synapse to release neurotransmitters and continue the message on to the brain. With the channels blocked, the result is that the message is not sent to the brain (4)). However, the most promising advances in pain relief treatment are those aimed at treating specific components and/or causes for pain. Drugs that regenerate damaged nerves such as Prosaptide TX14 (a) or drugs that target specific pain-causing enzymes such as Celebrex are important developments because they are more effective for treating the type of pain the patient is experiencing (phantom pain, inflamed joints respectively(4). Although we are far from eliminating chronic pain, we have made vast improvements in pain management. With the development of drugs that are specific to certain pain, we are moving closer to a time when we will be free from Dickinson's empty, blank pain.

WWW Sources

1)NINDS_Chronic Pain

2)Nociceptors and Pain

3)Insights on Human Health

4)New Discoveries and Treatments offer Hope

5)New Target Identified for Chronic Pain Therapy

6)New Neuropathic Pain

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