Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibromyalgia is a form of non-articular rheumatism characterised by long term (>3 months) and widespread musculoskeletal aching, stiffness and pressure hyperalgesia at characteristic soft tissue sites, called soft tissue tender points. The biophysiology of fibromyalgia, however, has remained elusive and the treatment remains mainly empirical. This article reviews the neuroendocrine-immune pathophysiology of fibromyalgia. There is no major evidence that fibromyalgia is accompanied by activation of the inflammatory response system, by immune activation or by an inflammatory process. There is some evidence that fibromyalgia is accompanied by some signs of immunosuppression, suggesting that immunomodifying drugs could have potential in the treatment of fibromyalgia. Recent trials with cytokines, such as interferon-alpha, have been undertaken in patients with fibromyalgia. Immunotherapy with these agents, however, may induce symptoms reminiscent of fibromyalgia and depression in a considerable number of patients. Lowered serum activity of prolyl endopeptidase (PEP), a cytosolic endopeptidase that cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass, may play a role in the biophysiology of fibromyalgia through diminished inactivation of algesic and depression-related peptides, e.g. substance P. Trials with PEP agonists could be worthwhile in fibromyalgia. The muscle energy depletion hypothesis of fibromyalgia is supported by findings that this condition is accompanied by lowered plasma levels of branched chain amino acids (BCAAs), i.e. valine, leucine and isoleucine. Since there is evidence that BCAA supplementation decreases muscle catabolism and has ergogenic values, a supplemental trial with BCAAs in fibromyalgia appears to be justified.
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PMID:Neuroendocrine and immune aspects of fibromyalgia. 1154 93

Topically applied capsaicin (CAS 404-86-4) induces the release of substance P, a neurotransmitter, from sensory C-fibres. In addition, there is a specific blockade of transport and de-novo synthesis of substance P. As a result, repeated applications of capsaicin bring about a long lasting desensitisation to pain (increase of pain threshold). The desensitising effect is fully reversible. The confirmed pharmacodynamic actions and a number of double-blind clinical studies indicate that local capsicum preparations are very suitable for the treatment of neuropathic pain or musculoskeletal disorders, with or without inflammatory components. In a double-blind, randomised parallel-group study a capsicum plaster was compared with a placebo for 3 weeks in 154 patients with non-specific back pain. Inclusion criteria were a history of back pain for a minimum period of 3 months and a degree of pain of 5 or more on an eleven grade visual analogue scale. The principal target variable consisted of the score of 3 combined pain scales. Secondary efficacy measures were tests of mobility, a disability index (in the context of Arhus low back rating scale) and global assessments by physicians and patients. For patients to be rated as responders their total pain score at the final examination after 3 weeks of treatment had to show a reduction by at least 30% of the baseline value. The study unequivocally achieved the target criterion with a rate of responders in the capsicum group of 60.8% against 42.1% in the placebo group (p = 0.0219). The sum of the 3 separate pain scales decreased more markedly in the capsicum group than in the placebo group (38.5% compared to 28.0%; p = 0.002). Relatively slight improvements of the impaired mobility and the functional status are explained by the characteristics of the disorder treated. The efficacy ratings by observers and patients was definitely in favour of capsicum. Adverse effects--mostly harmless and resolving spontaneously--were reported by 15 patients in the capsicum group and by 9 in the placebo group. The tolerance ratings by investigators and patients were superior to the placebo product. This, however, partly is due to the local pharmacological actions of the drug. As in comparably positive randomised studies with capsaicin cream in patients with osteoarthritis or fibromyalgia it was shown that a capsicum plaster preparation can also be used to advantage in chronic non-specific back pain.
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PMID:Capsicum pain plaster in chronic non-specific low back pain. 1176 91

Orofacial pain frequently originates from pathologic conditions in the masticatory muscles or temporomandibular joints (TMJs). The mediators and mechanisms that monitor pain and inflammation, centrally or peripherally, are of great interest in the search for new treatment modalities. The neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) have all been found at high levels in the synovial fluid of arthritic TMJs in association with spontaneous pain, while serotonin (5-HT) has been found in association with hyperalgesia/allodynia of the TMJ. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) have been found in arthritic TMJs, but not in healthy TMJs, in association with hyperalgesia/allodynia of the TMJ as well as spontaneous pain. Anterior open bite, which may be a clinical sign of TMJ destruction, has been found in association with high levels of CGRP, NPY, and IL-1 beta in the synovial fluid of the TMJ. Interleukin-1 beta has also been related to radiographic signs of joint destruction. Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are both present in the arthritic TMJ, and PGE2 has been shown to be associated with hyperalgesia/allodynia of the TMJ. Very little is known about pain and inflammatory mediators in muscles. However, we know that 5-HT and PGE2 are involved in the development of pain and hyperalgesia/allodynia of the masseter muscle in patients with fibromyalgia, whereas local myalgia (myofascial pain) seems to be modulated by other, as yet unknown mediators. Interaction between the peripheral nervous system (sensory and sympathetic nerves), the immune system, and local cells is probably of great importance for the modulation of pain and inflammation in the TMJ and orofacial musculature.
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PMID:Neuroendocrine, immune, and local responses related to temporomandibular disorders. 1188 48

Substance P (SP) is a neuropeptide which is abundant in the periphery and the central nervous system, where it is colocalized with other neurotransmitters such as serotonin or dopamine. SP has been proposed to play a role in the regulation of pain including migraine and fibromyalgia, asthma, inflammatory bowel disease, emesis, psoriasis as well as in central nervous system disorders. This review summarizes our current knowledge of the role of SP in the pathogenesis of neuropsychiatric disorders with special emphasis on affective disorders including bipolar disorders. It also reviews current treatment approaches with neurokinin 1 receptor antagonists which appear to be promising drugs for the future treatment of affective disorders.
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PMID:Substance P and affective disorders: new treatment opportunities by neurokinin 1 receptor antagonists? 1189 70

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

The impressive pain relief experienced by sufferers of dystonia and spasticity from intramuscular injections of botulinum toxin suggested that patients with other chronic, musculoskeletal pain conditions also may benefit. However, there have been relatively few placebo-controlled studies of botulinum toxin in such non-neurologic conditions as myofascial pain syndrome, chronic neck and low back pain, and fibromyalgia; the results of these studies have not been impressive. One explanation for the lack of positive findings may be the lack of clinically evident muscle spasms (overactivity), despite the presence of muscle tenderness, tightness, or trigger points. Clinical observations of pain relief from injections of botulinum toxin for dystonia and spasticity and its apparent efficacy in treating migraine suggest an anti-nociceptive action independent of its neuromuscular junction-blocking action. Evidence from animal experiments supports this notion, and other data provide plausible physiologic mechanisms in the periphery and central nervous systems. These involve modulation of the activity of the neurotransmitters glutamate, substance P, calcitonin gene-related peptide, enkephalins, and others. However, even if botulinum toxin is firmly established as an analgesic, there is insufficient clinical evidence of its efficacy in treating non-neurologic, chronic, musculoskeletal pain conditions.
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PMID:Botulinum toxin for the treatment of musculoskeletal pain and spasm. 1241 5

Substance P (SP) is a neuropeptide which is widely distributed in the periphery and the central nervous system (CNS), where it is co-localised with other neurotransmitters such as serotonin or dopamine and where it acts as a neuromodulator. SP has been proposed to play a role in the aetiopathology of asthma, inflammatory bowel disease, emesis, psoriasis, as well as neuropsychiatric disorders including pain syndromes (e.g. migraine and fibromyalgia) and affective disorders, anxiety disorders, schizophrenia and Alzheimer's disease. This review focuses on the role of SP in the pathogenesis of affective disorders. It summarises the current knowledge on measurements of SP in the CSF and serum in patients with depressive disorders or fibromyalgia, effects of SP-application in humans, SP-receptor expression in postmortem brains and the modulation of SP levels in the course of antidepressant treatment. It also discusses the promise of substance P-receptor antagonists (SPA) for the treatment of affective disorders and their proposed mechanism of action. In summary, much more research is needed to elucidate the role of SP in the pathogenesis of depression. SPA are promising as future drugs for the treatment of affective disorders, but current clinical trials have yet to be completed to draw a firm conclusion. Key words: substance P, neurokinin1-receptor, affective disorders, depression, review.
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PMID:Substance P and Substance P receptor antagonists in the pathogenesis and treatment of affective disorders. 1269 75

During the last 10 years, fibromyalgia (FM) research shifted focus from psychological and behavioral issues to sleep, nociception, and neuroendocrinology. Although there are still no definitive markers of the disease, a barrage of studies in physiological, psychological, and behavioral sciences have now dispelled the belief that FM is solely psychosomatic. Studies in the late 1990s as well as in the early part of the current decade reaffirm earlier research that sleep abnormalities and alterations in nociception may partly be responsible for FM. While sleep research shows that FM patients typically are deficient in stage IV (restorative) sleep, most current studies in nociception now affirm that patients with FM exhibit low serum serotonin in combination with increased substance P levels in the cerebrospinal fluid. Although there is still no cure, treatment aimed at promoting sleep, interrupting nociception, and actively involving patient and family in FM management can bring lifetime control for the disease.
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PMID:Fibromyalgia: evolving concepts and management in primary care settings. 1286 52

Modern management of fibromyalgia (FM) requires a holistic approach, which includes nonpharmacologic strategies (both exercise and behavioral strategies) and pharmacologic treatment. Despite only partial effects in some patients, tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal antiinflammatory drugs, analgesics and opioids are in use. The use of antiepileptic drugs and antispasticity agents is mainly supported by anecdotal data. Three other classes of agents are currently thought to have useful potentials. N-methyl-D-aspartate-(NMDA-)mediated neurotransmission may play an important role in mediating wind-up and related phenomena in pain pathways. Recent studies have demonstrated that NMDA receptor antagonists improve pain symptoms in FM. But a poor side effect profile represents a significant problem. Cerebrospinal fluid substance P concentrations are significantly elevated in FM patients, but the analgesic potential of neurokinin-1 (NK1) receptor antagonists did not meet early expectations. Tropisetron, a 5-HT3 receptor antagonist, was tested in a multicenter, double-blind, randomized, placebo-controlled trial including 403 patients. In those receiving 5 mg tropisetron, 39.2% fulfilled the response criterion (pain reduction 35%) as compared to 26.2% in the placebo group (p=0.033). On 10 and 15 mg, the responder rates were smaller and statistically not significant. A total of 78 responders to therapy were followed up for 12 months. After the end of treatment, pain intensity rose within one month in all 4 groups. Patients having received 5 or 10 mg showed a less pronounced increase in pain. In addition, even 12 months after stopping treatment, pain was still markedly below baseline levels in the 5 and 10 mg groups.
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PMID:[What's new in the therapy of fibromyalgia?]. 1464 17

Fibromyalgia has been called a "stress-related disorder" due to the onset and exacerbation of symptoms in the context of stressful events. Evidence suggests that inhibition of tonic pain is mediated by activation of mesolimbic dopamine neurons, arising from the cell bodies of the ventral tegmental area and projecting to the nucleus accumbens. This pain-suppression system is activated by acute stress, via the release of endogenous opioids and substance P within the ventral tegmental area. However, prolonged exposure to unavoidable stress produces both reduction of dopamine output in the nucleus accumbens and development of persistent hyperalgesia. It is proposed that a stress-related reduction of dopaminergic tone within the nucleus accumbens contributes to the development of hyperalgesia in the context of chronic stress and thus plays a role in the pathogenesis of fibromyalgia. A stress-related dysfunction of mesolimbic dopaminergic activity might serve as the basis for other fibromyalgia-associated phenomena as well.
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PMID:Stress and dopamine: implications for the pathophysiology of chronic widespread pain. 1497 15


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