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)

The present article concentrates on mechanisms that lead to the excitation of nociceptors in soft tissues and nociceptive neurones in the spinal dorsal horn. These mechanisms may contribute to the so-called unspecific low back pain. Properties of nociceptors in soft tissues: A nociceptive ending in soft tissue contains a multitude of receptor molecules in its membrane. The molecular receptors include binding sites for algesic substances that are released during painful stimulation or pathologic alterations of the tissue: bradykinin (BK), serotonin (5-HT), prostaglandin E2 (PG E2), adenosine triphosphate (ATP) and protons (H(+)). The excitation and sensitisation of nociceptors by these substances can be explained by the binding of the substances to the receptor molecules in the membrane of the receptive ending and ensuing opening of ion channels or activation of metabolic cascades. Purinergic receptor molecules in the membrane of nociceptors are activated by ATP. These receptors may be of particular importance for deep somatic pain, because ATP is present in large amounts in muscle tissue and is released during muscle damage. ATP-sensitive nociceptors appear to be distinct from nociceptors that can be excited by protons. The conduction of nociceptive information from muscle to the spinal cord is partly carried by unmyelinated fibres that possess tetrodotoxin-resistant (TTX-r) Na(+)-channels. Therefore, a drug that specifically blocks TTX-r Na(+)-channels would be a new attractive tool in the treatment of patients with deep somatic pain. Chronic muscle lesions such as a myositis have been shown to be associated with a higher innervation density of the tissue with free nerve endings that contain the neuropeptide substance P (SP). Many of these endings are likely to be nociceptors. Since a painful stimulus that acts on a muscle with increased nociceptor density will excite more nociceptors and elicit more pain, the increase in nociceptor density constitutes a peripheral mechanism for hyperalgesia. In muscle free nerve endings - many of which are nociceptive - the neuropeptides SP, calcitonin gene-related peptide (CGRP) and somatostatin have been shown to be present. These substances are released from the receptive endings in muscle when they are stimulated. SP and CGRP have a strong effect on blood vessels and induce local vasodilatation and oedema. The local oedema in the vicinity of the nociceptor is associated with the release of BK from plasma proteins, which increases the excitability of the nerve ending (see below). Thus, a local vicious cycle forms that may contribute to the formation of trigger points. Sensitisation of nociceptors and peripheral hyperalgesia: Nociceptors are easily sensitised, i.e. following a conditioning stimulus they are more sensitive to the unconditioned stimulus. In animals and humans, the responses to injections of BK can be increased by 5-HT or PG E2. The responses of muscle nociceptors to mechanical stimuli are likewise enhanced after administration of BK. During overuse, ischemia or inflammation of soft tissues, the tissue concentrations of BK, PG E2, and 5-HT are elevated and sensitise muscle nociceptors. A sensitised nociceptor is excited and elicits pain when innocuous mechanical stimuli act on the muscle, e.g. during contractions or stretch. Therefore, in chronically altered soft tissues, weak everyday stimuli are likely to cause pain. Mechanisms at the spinal level: In experiments on rats in which a myositis of the gastrocnemius-soleus (GS) muscle was induced experimentally, the effects of a peripheral painful lesion on the discharge behaviour of sensory dorsal horn neurones were studied. One of the main effects of the myositis was an expansion of the input (target) region of the muscle nerve, i.e. the population of dorsal horn neurones responding to an electrical standard stimulus applied to the GS muscle nerve grew larger. One reason for the myositis-induced expansion of the input region is hyperexcitability of the neurones caused by the release of SP and glutamate from the spinal terminals of muscle afferents with ensuing activation of NMDA channels in dorsal horn neurones (central sensitisation). The central sensitisation is of clinical importance because it can explain the hyperalgesia and spread of pain in patients. In contrast to excitability, the resting activity of dorsal horn neurones - which is likely to induce spontaneous pain in patients - does not appear to depend on the release of SP and glutamate but on the concentration of nitric oxide (NO) in the spinal cord. A pharmacological block of the NO synthesis led to a significant increase in background activity without affecting the excitability of the dorsal horn neurones. Such an increase in background activity was observed exclusively in nociceptive neurones, i.e. a local lack of NO in the spinal cord induces spontaneous pain. According to data from animal experiments, a decrease in the spinal NO concentration occurs as a sequel of a chronic muscle lesion; therefore, a lack of NO is a probable factor for the induction of chronic spontaneous pain. Normally, lesion-induced pain subsides and does not develop into chronic pain. The mechanisms governing the return to normal neuronal behaviour after a peripheral lesion are not well studied. Probably, the activation of inhibitory mechanisms, e.g. increased spinal synthesis of GABA or elevated activity of the descending antinociceptive system contribute to the restoration of normal function. The final step in the transition from acute to chronic pain are structural changes that perpetuate the functional changes. In the rat myositis model, an increase in the number of synapses on the surface of NO-snythesizing cells was present 8 h following induction of the myositis. These data show that structural changes appear quite early in the development of a painful disorder. A novel hypothesis for the development of chronic pain states that a strong nociceptive input to the spinal cord leads to cell death predominantly in inhibitory interneurones. Most of these interneurones are assumed to be tonically active; when their number decreases, the nociceptive neurones are chronically disinhibited and elicit continuous pain also in the absence of a noxious stimulus.
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PMID:[Pathophysiology of low back pain and the transition to the chronic state - experimental data and new concepts]. 1179 44

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

Discogenic low back pain is a common cause of disability, but its pathogenesis is poorly understood. We collected 19 specimens of lumbar intervertebral discs from 17 patients with discogenic low back pain during posterior lumbar interbody fusion, 12 from physiologically ageing discs and ten from normal control discs. We investigated the histological features and assessed the immunoreactive activity of neurofilament (NF200) and neuropeptides such as substance P (SP) and vasoactive-intestinal peptide (VIP) in the nerve fibres. The distinct histological characteristic of the painful disc was the formation of a zone of vascularised granulation tissue from the nucleus pulposus to the outer part of the annulus fibrosus along the edges of the fissures. SP-, NF- and VIP-immunoreactive nerve fibres in the painful discs were more extensive than in the control discs. Growth of nerves deep into the annulus fibrosus and nucleus pulposus was observed mainly along the zone of granulation tissue in the painful discs. This suggests that the zone of granulation tissue with extensive innervation along the tears in the posterior part of the painful disc may be responsible for causing the pain of discography and of discogenic low back pain.
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PMID:The pathogenesis of discogenic low back pain. 1568 39

Astronauts exposed to microgravity frequently report low back pain. This pain is described as moderate to severe in intensity. This condition warrants investigation as low back pain may hinder an astronaut's ability to perform challenging tasks by virtue of disruption of sleep and, subsequently, mental concentration. It is reported by astronauts that a "fetal tuck position" described as knees to chest position relieves back pain. It is possible that the pathogenesis of back pain in microgravity is discogenic (or mechanical) and somatic, referred from the sinuvertebral nerves due to excessive expansion of the lumbar intervertebral discs associated with reduction of gravitational compressive loads in space. The fetal tuck position may increase lumbar intervertebral disc hydrostatic pressure by flexion and transfer of spinal compressive forces toward the anterior region of the lumbar discs, subsequently reducing disc volume. Moreover, this position may reduce Type IV mechanoreceptor facilitation and nerve impulse propagation from the sinuvertebral nerves of the annulus fibrosus, and thus diminish low back pain perception. Elongated posterior soft tissues (apophyseal joint capsules and ligaments) with spinal flexion may potentially stimulate Type I and II mechanoreceptors. This neutralizes substance P in the spinal cord dorsal horn by increasing naturally occurring opioids such as enkephalins. Separately, other investigators have reported a higher incidence of herniated discs (HNP) in astronauts postflight. Further studies of countermeasures are recommended to prevent excessive spinal elongation and disc expansion, reduce low back pain in microgravity, and simulate 1-G disc homeostasis, which may also help prevent HNPs postflight.
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PMID:Pathophysiology of low back pain during exposure to microgravity. 1845 93

Fibromyalgia is the diagnosis given to individuals with chronic widespread musculoskeletal pain for which no alternative cause, such as tissue inflammation or damage, can be identified. Fibromyalgia is now believed to be, at least in part, a disorder of central pain processing that produces heightened responses to painful stimuli (hyperalgesia) and painful responses to nonpainful stimuli (allodynia). Aberrations in central pain processing may also be partly responsible for symptoms experienced in several chronic pain disorders that coaggregate with fibromyalgia, which is itself a product of genetic and environmental factors. Thus, aberrational central pain processing is implicated in irritable bowel syndrome, temporomandibular disorder, chronic low back pain, and certain other chronic pain disorders. Fibromyalgia and related disorders appear to reflect deficiencies in serotonergic and noradrenergic, but not opioidergic, transmission in the central nervous system. The heightened state of pain transmission may also be owing to increases in pronociceptive neurotransmitters such as glutamate and substance P. In some cases, psychological and behavioral factors are also in play. Although the overlapping symptomatology between fibromyalgia and related disorders may present diagnostic challenges, proper examination and observation can help clinicians make an accurate diagnosis. In recent years, the vastly improved understanding of the mechanism underlying fibromyalgia and the related spectrum of diseases has fostered rapid advances in the therapy of these chronic pain disorders by both pharmacologic and nonpharmacologic interventions.
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PMID:Fibromyalgia: an overview. 1996 94

The sacroiliac joint (SI joint) is a known source of low back pain. In the absence of validated physical signs and imaging studies, the diagnosis of SI joint pain can be secured by positive response to SI joint intra-articular infiltration with local anesthetics. The current anatomical and histological knowledge concerning intra-articular structures of the sacroiliac joint is insufficient to explain the efficacy of this infiltration. Consequently, this study was undertaken to detect the intra-articular presence of substance P and calcitonin gene-related peptide (CGRP) positive nerve fibers, providing indirect evidence of nociceptive innervation of the SI joint. Free-floating sections, obtained from iliac and sacral cartilage and subchondral bone of the SI joint and adjacent ligamentous tissue, of 10 human cadavers were studied immunohistochemically. Tissue of nine human cadavers showed the presence of substance P and CGRP immunoreactivity in the superficial layer of sacral and iliac cartilage, and the surrounding ligamentous structures. Subchondral bone reacted weakly to the antisera used. These findings support the view that the SI joint may be capable of intra-articular nociception and may explain the positive response to the intra-articular deposition of local anesthetic.
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PMID:Possible nociceptive structures in the sacroiliac joint cartilage: An immunohistochemical study. 2001 92

The available data on the innervation of the thoracolumbar fascia (TLF) are inconsistent and partly contradictory. Therefore, the role of the fascia as a potential source of pain in the low back is difficult to assess. In the present study, a quantitative evaluation of calcitonin gene-related peptide (CGRP) and substance P (SP)-containing free nerve endings was performed in the rat TLF. A preliminary non-quantitative evaluation was also performed in specimens of the human TLF. The data show that the TLF is a densely innervated tissue with marked differences in the distribution of the nerve endings over the fascial layers. In the rat, we distinguished three layers: (1) Outer layer (transversely oriented collagen fibers adjacent to the subcutaneous tissue), (2) middle layer (massive collagen fiber bundles oriented obliquely to the animal's long axis), and (3) inner layer (loose connective tissue covering the paraspinal muscles). The subcutaneous tissue and the outer layer showed a particularly dense innervation with sensory fibers. SP-positive free nerve endings-which are assumed to be nociceptive-were exclusively found in these layers. Because of its dense sensory innervation, including presumably nociceptive fibers, the TLF may play an important role in low back pain.
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PMID:Sensory innervation of the thoracolumbar fascia in rats and humans. 2183 50

In this review of recent research on prenatal exercise, studies from several different countries suggest that only approximately 40% of pregnant women exercise, even though about 92% are encouraged by their physicians to exercise, albeit with some 69% of the women being advised to limit their exercise. A moderate exercise regime reputedly increases infant birthweight to within the normal range, but only if exercise is decreased in late pregnancy. Lower intensity exercise such as water aerobics has decreased low back pain more than land-based physical exercise. Heart rate and blood pressure have been lower following yoga than walking, and complications like pregnancy-induced hypertension with associated intrauterine growth retardation and prematurity have been less frequent following yoga. No studies could be found on tai chi with pregnant women even though balance and the risk of falling are great concerns during pregnancy, and tai chi is one of the most effective forms of exercise for balance. Potential underlying mechanisms for exercise effects are that stimulating pressure receptors during exercise increases vagal activity which, in turn, decreases cortisol, increases serotonin and decreases substance P, leading to decreased pain. Decreased cortisol is particularly important inasmuch as cortisol negatively affects immune function and is a significant predictor of prematurity. Larger, more controlled trials are needed before recommendations can be made about the type and amount of pregnancy exercise.
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PMID:Prenatal exercise research. 2272 40

Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors.
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PMID:Innervation changes induced by inflammation of the rat thoracolumbar fascia. 2600 35

There is evidence that low back pain may originate from a peridural membrane (PDM) at the inferior and medial aspect of neural foramen of the lumbar spine. The objective of this investigation was to determine if this membrane contains neural elements suggestive of sensory innervation with nociceptive function. Spines of four embalmed and three non-embalmed human cadavers were dissected using a sagittal approach to the neural foramen. Seventeen samples of the peridural membrane overlying the neural foramen were collected for immunohistochemistry (IHC) examination by light microscopy and transmission electron microscopy (TEM). Chromagin tagged antibodies to protein gene product 9.5 (PGP9.5) and S-100, and fluorescent antibodies to substance P and calcitonin gene related peptide (CGRP) were used to label neural structures in tissue sections cut from paraffin embedded blocks. This approach allows good visualization of all neural elements, small sensory, and nociceptive nerve fibers in particular. Neural elements were found in all samples. Marked presence of small nerve fibers was observed in 12 of 15 samples. IHC and TEM evaluation revealed myelinated as well as unmyelinated fibers in the peridural membrane. CGRP and substance P immunoreactive fibers indicative of nociceptive function were abundant. These findings confirm and expand evidence that the peridural membrane in human is well innervated and contains sensory nociceptive nerve fibers suggestive of a nociceptive function of the membrane.
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PMID:The Peridural Membrane of the Human Spine is Well Innervated. 2686 45


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