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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent work in the learned helplessness paradigm suggests that neuronal sensitization and fatigue processes are critical to producing the behavioral impairment that follows prolonged exposure to an unsignaled inescapable stressor such as a series of electric tail shocks. Here we discuss how an interaction between serotonin (5-HT) and corticosterone (CORT) sensitizes GABA neurons early in the pretreatment session with inescapable shock. We propose that this process eventually depletes GABA, thus removing an important form of inhibition on excitatory glutamate transmission in the amygdala, hippocampus, and frontal cortex. When rats are re-exposed to shock during shuttle-escape testing 24 hrs later, the loss of inhibition (as well as other excitatory effects) results in unregulated excitation of glutamate neurons. This state of neuronal over-excitation rapidly compromises metabolic homeostasis. Metabolic fatigue results in compensatory inhibition by the nucleoside adenosine, which regulates neuronal excitation with respect to energy availability. The exceptionally potent form of inhibition associated with adenosine receptor activation yields important neuroprotective benefits under conditions of metabolic failure, but also precludes the processing of information in fatigued neurons. The substrates of adaptive behavior are removed; performance deficits ensue.
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PMID:Stressor controllability and learned helplessness research in the United States: sensitization and fatigue processes. 1206 65

Pain is perceived, transmitted, processed and modulated within an extensive network of neurotransmitters and hormones. Despite increasing knowledge about the biologic principles, even on the molecular level, the more we learn about the precise mechanisms of their interactions the more questions arise. It is also pertinent to remember that clinical scientists studying pain modulating pharmacologic agents always have to consider possible placebo effects [57-61]. Most of our knowledge regarding the function of neurotransmitter systems in the CNS has been provided by animal studies. Thus we cannot be sure that they have exactly parallel counterparts in humans. For instance, animal studies suggest an inverse relationship between brain and spinal cord concentrations of substance P. If these observations are converted to an interpretation of human fibromyalgia, low brain-tissue levels of both serotonin and substance P should be expected, while spinal cord serotonin concentrations would be low and spinal cord substance P would be high [1]. There is good evidence that 5-HT, its receptors, and their interactions with other neurotransmitters are essential for nociception and antinociception. The activities of 5-HT receptors can be studied by agonist and in humans especially by antagonist use. But even with a direct spinal application of selective agonists and antagonists, observations may still be confounded by (1) dose, as there can be a dose-dependent activation of different receptor subtypes; (2) type of nociceptive tests (e.g., thermal versus pressure versus chemical models), which may have differences in the way they are regulated; and (3) influences due to effects on temperature, blood flow or motor function. With this potential for variability, it is perhaps not surprising that there is some variability in the results of studies reporting on the effects of various 5-HT agonists and antagonists on nociceptive transmission within the spinal cord [62]. For instance, different 5-HT3 receptor densities could exist in various neuronal systems, one density type being completely inhibited at low concentrations, and the others only at higher concentrations of 5-HT3 receptor antagonists, thus resulting in contrary effects. Finally, the "endogeneous 5-HT tone" may greatly influence agonist and antagonist action. Considering this complexity of serotonin-mediated reactions, it is not surprising that treatment of pain by 5-HT3 receptor antagonists appears to yield inconsistent results. As fibromyalgia is now regarded as a pain amplification syndrome with a broad variety of additional nonpain symptoms, the interrelations are complicated even more. Fibromyalgia associated symptoms (e.g., fatigue, insomnia, and irritable bowel syndrome) can be modulated by 5-HT3 receptor antagonists. From the data evaluated so far, there is evidence that 5-HT3 receptor antagonists provide significant benefit in some fibromyalgia patients. In our practice, the data justify a careful application in clinical use according to the study results. The dosage, route of application, long term adverse reactions and duration of therapy still need to be studied in greater detail. Recently reported adverse events from therapy of irritable bowel syndrome with alosetron [63-67] provide a note for caution before hastily using 5-HT3 receptor antagonists without more studies. One can surmise that, much as the biochemistry of depression has been elucidated by the development of the SSRIs, a greater understanding of the role of 5-HT3 receptor antagonists in treating fibromyalgia patients may provide some insights into disease mechanisms of this enigmatic disorder.
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PMID:Current experience with 5-HT3 receptor antagonists in fibromyalgia. 1212 20

Rizatriptan is an orally active serotonin 5-HT(1) receptor agonist that potently and selectively binds to 5-HT(1B/1D) subtypes. Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms. Rizatriptan is generally well tolerated, and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2-4%). In conclusion, rizatriptan is an effective drug for the acute treatment of moderate or severe migraine. Oral rizatriptan 5 and 10mg have shown greater efficacy than placebo in providing pain relief, an absence of pain, relief from associated symptoms, normal functional ability and an improvement in patient quality of life. Earlier results showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recent studies have shown that rizatriptan 10mg provides faster pain relief and a higher percentage of patients with an absence of pain and normal functional ability at 2 hours than naratriptan 2.5mg or zolmitriptan 2.5mg. The efficacy of rizatriptan is retained when used in the long term, and the drug is generally well tolerated. Although well designed studies comparing rizatriptan with almotriptan, eletriptan and frovatriptan would further define the position of rizatriptan, current data suggest that rizatriptan should be considered as a first-line treatment option in the management of migraine.
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PMID:Spotlight on rizatriptan in migraine. 1226 63

Rizatriptan and sumatriptan are selective 5-HT(1B/1D) receptor agonists for theacute treatment of migraine. For oral formulations, the time to maximum plasma concentration is reached earlier with rizatriptan than with sumatriptan (1 h versus 2-2.5 h) and rizatriptan has greater bioavailability than sumatriptan (45% versus 15%). These pharmacological advantages appear to translate into a faster onset of action and a better overall response for oral rizatriptan versus oral sumatriptan. The two drugs have been directly compared in randomized, double-blind, placebo-controlled clinical trials of patients with moderate or severe migraine attacks. Rizatriptan 10 mg was generally superior to sumatriptan on a measure of time-to-pain-relief within 2 h, where pain relief was defined as a reduction of pain to mild or none (odds ratio for rizatriptan versus sumatriptan 100 mg = 1.21; odds ratios for rizatriptan 10 mg versus sumatriptan 50 mg = 1.14 and 1.10 in two studies). Rizatriptan 10 mg was also superior to sumatriptan on the International Headache Society recommended endpoint of the percentage of patients pain free at 2 h (40% for rizatriptan 10 mg, 33% for sumatriptan 100 mg, and 35% for sumatriptan 50 mg). Further advantages for rizatriptan were seen on stringent outcome measures of the percentage of patients who were completely free of all symptoms at 2 h, patient satisfaction with medication at 2 h, and 24-h sustained pain-free response. 5-HT(1B/1D) receptor agonists are contraindicated in patients with coronary artery disease because of their potential to cause vasoconstriction. In clinical trials which excluded such patients, rizatriptan and sumatriptan were both well-tolerated. The most common side-effects on both drugs occurred in <10% of patients and consisted of dizziness, drowsiness, and asthenia/fatigue. The adverse events were usually mild or moderate in severity and short-lasting.
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PMID:Rizatriptan: pharmacological differences from sumatriptan and clinical results. 1246 79

Frovatriptan is a 5-HT(1B/1D) agonist demonstrating consistently effective headache relief at a low dose of 2.5 mg. A striking pharmacokinetic characteristic is its long half-life of 25 h. This is balanced by an average Tmax of 2-3 h, a low degree of lipophilicity and a low oral bioavailability of 24-30%. Fifty per cent of the drug is renally excreted and the rest is partially metabolized by P450 CYP 1A2. In three short-term multicentre, double-blind, placebo-controlled phase III trials, the 2 h headache response for 2.5 mg frovatriptan varied from 36 to 46% (placebo 21-27%). The 4 h headache responses were considerably higher--up to 65%. Thirty-five per cent of patients were consistent rapid responders. The recurrence rate was 10-25%. In addition to effective and prolonged relief of head pain, frovatriptan reduced associated migraine symptoms such as nausea, photophobia and phonophobia. There was an excellent tolerability profile with the incidence of adverse events for frovatriptan only slightly higher than placebo. The most commonly reported adverse events for both frovatriptan and placebo were dizziness, nausea, headache and fatigue.
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PMID:Frovatriptan: pharmacological differences and clinical results. 1246 82

Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.
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PMID:The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. 1246 36

We have studied 12 recreationally active men to measure their responses to exercise in the heat and relate these to measures of hypothalamic function explored with a buspirone [5-hydroxytryptamine 1A (5-HT(1A)) agonist, dopaminergic D(2) antagonist] neuroendocrine challenge, with and without pretreatment with pindolol (5-HT(1A) antagonist). Pindolol treatment allowed the serotonergic and non-serotonergic components of prolactin release to be distinguished. Subjects exercised at 73 (5)% maximal rate of oxygen uptake (VO(2max)) until volitional fatigue at 35 degrees C (relative humidity, 30%). On another two occasions they underwent a buspirone challenge [0.5 mg (kg body mass)(-1)], once with, and once without, pindolol [0.5 mg (kg body mass)(-1)] pretreatment and the circulating plasma concentrations of prolactin were measured for the next 2.5 h. Rectal temperature increased throughout exercise, whilst mean skin temperature remained constant. There was a wide inter-subject variation in prolactin response to the neuroendocrine challenges. The proportion of the prolactin response to buspirone attributable to a non-serotonergic component (most likely dopaminergic) correlated both with exercise duration (r=0.657, P=0.028), rectal temperature at fatigue (r=0.623, P=0.041) and the rate of temperature rise (r=-0.669, P=0.024). Our results suggest that high activity of the dopaminergic pathways in the hypothalamus is a predictor of exercise tolerance in the heat.
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PMID:Responses to exercise in the heat related to measures of hypothalamic serotonergic and dopaminergic function. 1268 6

Considerable evidence points towards a prominent role for central nervous system (CNS) mechanisms in the pathogenesis of chronic fatigue syndrome (CFS), a disorder characterized chiefly by persistent, often debilitating, fatigue. We wished to characterize circulating profiles of putative amino acid modulators of CNS 5-hydroxytryptamine (5-HT; serotoninergic) and dopaminergic function in CFS patients at rest, as well as during symptom-limited exercise and subsequent recovery. Groups of 12 CFS patients and 11 age- and sex-matched sedentary controls, with similar physical activity histories, underwent ramp-incremental exercise to the limit of tolerance. Plasma amino acid concentrations, oxygen uptake and ratings of perceived exertion were measured at rest, and during exercise and recovery. Peak oxygen uptake was significantly lower in the CFS patients compared with controls. Rating of perceived exertion in the patients was higher at all time points measured, including at rest, relative to controls. Levels of free tryptophan (free Trp), the rate-limiting 5-HT precursor, were significantly higher in CFS patients at exhaustion and during recovery, whereas concentrations of branched-chain amino acids (BCAA) and large neutral amino acids (LNAA) were lower in CFS patients at exhaustion, and for LNAA also during recovery. Consequently, the [free Trp]/[BCAA] and [free Trp]/[LNAA] ratios were significantly higher in CFS patients, except at rest. On the other hand, levels of tyrosine, the rate-limiting dopaminergic precursor, were significantly lower at all time points in the CFS patients. The significant differences observed in a number of key putative CNS 5-HT and dopaminergic modulators, coupled with the exacerbated perception of effort, provide further evidence for a potentially significant role for CNS mechanisms in the pathogenesis of CFS.
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PMID:Chronic fatigue syndrome: new evidence for a central fatigue disorder. 1270 66

Serotonin (5-hydroxytryptamine, 5-HT)-containing neurons in the midbrain directly innervate corticotropin-releasing hormone (CRH)-containing cells located in paraventricular nucleus of the hypothalamus. Serotonergic inputs into the paraventricular nucleus mediate the release of CRH, leading to the release of adrenocorticotropin, which triggers glucocorticoid secretion from the adrenal cortex. 5-HT1A and 5-HT2A receptors are the main receptors mediating the serotonergic stimulation of the hypothalamic-pituitary-adrenal axis. In turn, both CRH and glucocorticoids have multiple and complex effects on the serotonergic neurons. Therefore, these two systems are interwoven and communicate closely. The intimate relationship between serotonin and the hypothalamic-pituitary-adrenal axis is of great importance in normal physiology such as circadian rhythm and stress, as well as pathophysiological disorders such as depression, anxiety, eating disorders, and chronic fatigue.
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PMID:Serotonin and the neuroendocrine regulation of the hypothalamic--pituitary-adrenal axis in health and disease. 1285 56

Early human pharmaco-EEG and subsequent sleep laboratory studies identified trazodone, a 5-HT(2) antagonist and 5-HT reuptake inhibitor (SARI), as an antidepressant with therapeutic effects on its target symptoms depressed mood, anxiety and insomnia. On the occasion of the introduction of a controlled-release (CR) formulation (Trittico 150 mg retard, marketed in Austria by CSC Pharmaceuticals Handels GmbH, Vienna, Austria) in Austria in July 2000, a multi-center, open, clinical post-marketing study on the therapeutic effects, safety and target symptoms of trazodone CR in depression was carried out at 80 offices of Austrian neuropsychiatrists. 549 outpatients (63% females) of all age groups suffering from five different subtypes of depression were enrolled in the study. After a 2-week fixed dose-titration regimen up to 150 mg and a 4-week adjustment period to the optimum dose, 66% of the patients remained on 150 mg, 20% increased the dose and 11% decreased it. Only 3.7% discontinued treatment. Rating by the neuropsychiatrists based on the Clinical Global Impression showed very much to much improvement in 78.3% of the patients, and no change or a deterioration in only 3.6%. In the Hamilton Depression Scale (HAMD) a statistically significant improvement from a baseline score of 21 to a score of 14 after 2 weeks was found, and a normalization to a score of 8 after 6 weeks. Therapeutic effects were similar in the five groups suffering from different subtypes of depression and in patients with and without comedication. Self-rating by the patients based on the Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Anxiety Scale (SAS) also showed a significant improvement in the 2nd and 6th week of therapy. Evaluation of the target symptoms of trazodone by ranking the most improved symptoms identified insomnia as the most improved psychopathological item in all three scales. While in the observer ratings also suicidal tendencies and weight loss were found much improved, in the self-rated Zung SDS sadness and loss of drive came second and third in the improvement ranking, in the self-rated Zung SAS anxiety and the feeling of falling apart. Tolerability was very good. In the 2nd week only 16.9% and in the 6th week only 7.6% of the patients reported side effects, mostly characterized by tiredness and rarely by nausea and vertigo. The present clinical study is in agreement with previous studies identifying trazodone as a safe and effective antidepressant, specifically regarding its target symptoms insomnia, depression and anxiety. It also confirms our own early predictions based on neurophysiological investigations concerning the mode of action of the drug.
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PMID:Confirmation of the neurophysiologically predicted therapeutic effects of trazodone on its target symptoms depression, anxiety and insomnia by postmarketing clinical studies with a controlled-release formulation in depressed outpatients. 1467 18


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