In the 1990s, researchers proposed that exposure to stressful conditions could alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes. Variations in HPA function are characterized by high levels of cortisol, which in turn is associated with the development of widespread pain. When cortisol excretion levels were measured in one research study, with a sample of forty-seven women diagnosed with FM compared to a control sample of fifty-eight healthy women of similar age, it was confirmed the women with FM excreted significantly lower cortisol levels than the healthy women. Other data in FM have demonstrated a blunted cortisol response to the stress of high-intensity exercise. Most recently, a lack of normal daily cortisol variation has been identified in FM.
Scientists theorize that Stage-4 sleep is critical to good nervous system function, because it is during that time the body releases needed neurochemicals. Deep sleep is thought to be critical in resetting levels of the neuropeptide Substance P, which is a key transmitter of pain to the brain. People with FM lack slow-wave sleep and often experience other factors that interfere with Stage-4 sleep such as pain, depression, anxiety, lack of serotonin, and RLS. According to the sleep disturbance hypothesis, a trauma or illness that causes sleep disturbance might trigger FM. Remember that chemical pain processing can be viewed as two opposing forces. The first process involves chemical messages sent to the brain that are interpreted as pain, and the second is a chemical response from the brain that attempts to inhibit the pain message. Pain sensations travel from the periphery to an area of the spinal cord called the dorsal horn, where the release of any chemicals, including Substance P, takes place. The chemicals released by the spinal cord work to attach themselves to neuroreceptors. Substance P binds itself to a receptor called NK1. The chemical message then travels upward along the spinal cord to the brain where the message is interpreted as pain. In response, the brain returns neurochemicals, such as serotonin, norepinephrine, zinc, and opi-oids, to the spinal cord where Substance P had been released. At this point there is a "down regulation" of Substance P that calms the perception of pain. Researchers believe that in FM this process is disrupted. A patient may have either too much Substance P or too few inhibitor chemicals. It is likely an imbalance of these chemicals plays an important part in the amplified pain cycle experienced in FM.
Another hypothesis suggests that reduced sleep leads to reduced production of human growth hormone (HGH) during slow-wave sleep. Many people with FM produce inadequate levels of HGH, and tests show that hormones under the direct or indirect control of HGH, including insulin-like growth factor 1 (IGF-1), cortisol, leptin, and neuropeptide Y are abnormal in people with FM. Most HGH is made during deep sleep, with additional pulsatile release throughout the day and in response to stress, such as vigorous exercise. Treatment with HGH has been shown to normalize IGF-1 and reduce symptoms in people with FM. Other medications have been demonstrated to improve HGH release in response to vigorous exercise but help only selected symptoms such as fatigue, sleep, anxiety, and ability to exercise. Research is ongoing regarding the best way to manipulate the HPA axis in order to return people with FM to better physical function.
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