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

Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants. Lesions of noradrenergic neurons, however, result in either normal or reduced pain behavior and variable changes in morphine antinociception, undermining the proposed association between noradrenaline (NA) deficiency and chronic pain (hyperalgesia). We used mice lacking the gene coding for dopamine beta-hydroxylase, the enzyme responsible for synthesis of NA from dopamine, to reexamine the consequences of a lack of NA on pain behavior. Here, we show that absence of NA in the central nervous system results in a substance P-mediated chronic hyperalgesia (decreased nociceptive threshold) to thermal, but not mechanical, stimuli and decreased efficacy of morphine. Contrary to studies that show substance P-mediated hyperalgesia requires intense stimuli, we found that even a mild stimulus is sufficient to evoke substance P-dependent hyperalgesia in the NA-deficient mice. Restoring central NA normalized both the nociceptive threshold and morphine efficacy, which is consistent with a tonic inhibitory effect of NA on nociceptive transmission. Unexpectedly, however, antagonists to the substance P receptor (the NK1 receptor) could achieve the same effect as NA replacement. We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation.
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PMID:The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline. 1180 10

The physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca2+ which stimulates nitric oxide synthase (NOS) and the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighboring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, mu- and delta-receptors either inhibit or potentiate NMDA receptor-mediated events, while kappa opioids antagonize NMDA receptor-mediated activity. Recently, CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus, eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive and locomotor components.
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PMID:Nociception, pain, and antinociception: current concepts. 1182 34

Long-term potentiation (LTP) in wide dynamic range (WDR) neurons in the dorsal horn has been suggested to contribute to central sensitization and the development of chronic pain. Indirect experimental evidence indicates an involvement of substance P (SP), in this respect. The aim of the present study was to monitor the extracellular level of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat during and after induction of LTP in WDR neurons in vivo. Electrophysiological recordings of single (WDR) neurons were performed in parallel with microdialysis in the dorsal horn under urethane-anaesthesia. The amount of SP-LI in the microdialysate was determined by radioimmunoassay. As previously shown, high frequency conditioning stimulation of the sciatic nerve induced an increased firing response of WDR neurons. An increased response to C-fibre stimulation, but not A-fibre stimulation, could be determined. A significant increase of the extracellular level of SP-LI in the dorsal horn was detected during, but not after, induction of LTP. These data suggest that SP may be involved in the induction of LTP by high frequency stimulation. However, the maintenance of spinal LTP following high frequency peripheral nerve stimulation does not seem to depend on an increased release of SP.
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PMID:Spinal substance P release in vivo during the induction of long-term potentiation in dorsal horn neurons. 1193 60

Neurogenic inflammation is elicited by activation of unmyelinated sensory neurons through noxious stimuli and subsequent release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. The nerve-mediated inflammatory responses in the tissue consist of hyperaemia and oedema which under some circumstances may be accompanied by pain. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases with uncertain etiology. Signs of inflammation and hyperalgesia associated with chronic pain syndromes such as migraine, arthritis and complex regional pain syndrome resemble the characteristics of neurogenic inflammation. By extrapolation of convincing evidence obtained in rodent models, neurogenic inflammation is assumed to contribute to diseases of the respiratory system, gastrointestinal tract, urogenital tract, and skin in humans. Since, however, highly selective substance P receptor antagonists, found to be effective against inflammation in rodents, failed to inhibit inflammatory processes in clinical trials, the hypothesis of an involvement of neurogenic inflammation in human diseases is discussed critically in this review. Beyond its primarily inflammatory character neurogenic inflammation can be regarded as a mechanism that activates protective responses, thus bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair.
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PMID:[Neurogenic inflammation. II. pathophysiology and clinical implications]. 1210 11

Chronic inflammatory conditions are associated with an upregulation of both substance P (SP) and neurokinin-1 (NK-1) receptors in the dorsal spinal cord. These receptors have been implicated in hyperalgesia as well as stress-induced analgesia. On the basis of the release of SP during chronic pain, and its rapid metabolism, we tested the hypothesis that SP metabolites regulate the synthesis of either SP or NK-1 receptors in the spinal cord. We measured expression of preprotachykinin mRNA and NK-1 receptor mRNA following intrathecally administered substance P(1-7) (SP1-7), the major metabolite of SP in rat, and following capsaicin, a compound known to induce release of endogenous SP. SP(1-7) and capsaicin each increased NK-1 receptor mRNA in the spinal cord (6 h) followed by an increase in NK-1 receptor-immunoreactivity (24 h and 1 week). D-SP(1-7), a D-isomer and antagonist of SP(1-7), did not mimic the effect of SP(1-7), indicating stereoselectivity. Instead, D-SP(1-7) prevented the upregulation of NK-1 receptor immunoreactivity that was induced by capsaicin injected intrathecally, suggesting that the effect of capsaicin is also mediated by SP N-terminal metabolites. In contrast, the decrease in SP synthesis produced by capsaicin was not dependent on SP metabolites as SP(1-7) failed to decrease either preprotachykinin mRNA content in dorsal root ganglia (6 h) or SP immunoreactivity in the lumbar spinal cord (24 h and 1 week). In addition, the effects of capsaicin on SP synthesis were not prevented by D-SP(1-7). Thus, SP metabolites, at times and doses that are antinociceptive, appear to enhance SP-mediated signal transduction by upregulating NK-1 receptor expression without affecting SP synthesis.
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PMID:Upregulation of neurokinin-1 receptor expression in rat spinal cord by an N-terminal metabolite of substance P. 1216 5

We investigated the response of chronic neck and shoulder pain to decompression of the carpal tunnel in 38 patients with whiplash injury. We also determined the plasma levels of substance P (SP) and calcitonin gene-related peptide (CGRP), which are inflammatory peptides that sensitise nociceptors. Compared with normal control subjects, the mean concentrations of SP (220 v 28 ng/l; p < 0.0001) and CGRP (400 v 85 ng/l; p < 0.0005) were high in patients with chronic shoulder and neck pain before surgery. After operation their levels fell to normal. There was resolution of neurological symptoms with improvement of pain in 90% of patients. Only two of the 30 with chronic neck and shoulder pain who had been treated conservatively showed improvement when followed up at two years. In spite of having neuropathic pain arising from the median nerve, all these patients had normal electromyographic and nerve-conduction studies. Chronic pain in whiplash injury may be caused by 'atypical' carpal tunnel syndrome and responds favourably to surgery which is indicated in patients with neck, shoulder and arm pain but not in those with mild symptoms in the hand. Previously, the presence of persistent neurological symptoms has been accepted as a sign of a poor outcome after a whiplash injury, but our study suggests that it may be possible to treat chronic pain by carpal tunnel decompression.
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PMID:Management of chronic pain in whiplash injury. 1293 21

The potential for administering substance P (SP) nocitoxins for the treatment of chronic pain has been identified. To characterize treatment protocols for the spinal cord or elsewhere, binding/internalization of these compounds at the cellular targets must be understood quantitatively. Thus, a kinetic model of SP binding and intracellular trafficking has been developed from data. The eight differential equation model describes surface binding between SP and neurokinin 1 receptor, clathrin-mediated endocytosis followed by spatial translation to a perinuclear endosome where SP is sorted from its receptor, SP degradation in late endosomes/early lysosomes, and return of sorted receptor to plasma membrane via recycling endosomes. With suitably optimized parameters, the model accounts for the kinetics of total, membrane-associated, and internalized SP in cells continuously exposed to SP, as well as the fractions of internalized SP remaining intact at 30 and 60 min. Simultaneously, the model accounts for the kinetics of internalization and receptor recycling after SP preloading of membrane and subsequent exposure to SP-free media. Rate constants (min(-1)) are: 0.034 +/- 0.004 (receptor off-rate), 0.15 +/- 0.03 (internalization), 0.048 +/- 0.003 (exit from sorting endosome), 0.062 +/- 0.008 (exit of labeled SP amino acids from prelysosome), and 0.029 +/- 0.004 (receptor return from recycling endosome to plasma membrane). The SP kinetics resemble those of transferrin and its receptor at the internalization step, but are several-fold slower in the sorting and recycling steps.
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PMID:A kinetic analysis of substance P trafficking. 1253 72

Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT' infusion (0.1 microl/min), the distribution of cytotoxicity in NK1 receptor-expressing neurons was predicted to reach an asymptotic limit at 6-8 h in the transverse direction at the level of the infusion cannula tip ( approximately 60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT' treatment was favored by a stable SP analog (half-life approximately 60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1 receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain.
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PMID:Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model. 1279 91

The antinociceptive effect of alpha(2)-adrenoceptor agonists is mediated by activation of descending inhibiting noradrenergic systems, which modulates 'wide-dynamic-range' neurones. Furthermore, they inhibit the liberation of substance P and endorphines and activate serotoninergic neurones. Despite this variety of antinociceptive actions, there is still little experience with alpha(2)-adrenoceptor agonists as therapeutic agents for use in chronic pain syndromes. Studies in animals and patients have shown that the transdermal, epidural and intravenous administration of the alpha(2)-adrenoceptor agonist clonidine reduces pain intensity in neuropathic pain syndromes for periods varying from some hours up to 1 month. Patients suffering from lancinating or sharp pain respond best to this therapy. Topically applied clonidine (200-300 microg) relieves hyperalgesia in sympathetically maintained pain. Epidural administration of 300 microg clonidine dissolved in 5 ml NaCl 0.9 % has also been shown to be effective. In patients suffering from cancer pain tolerant to opioids, pain control has proved possible again with combinations of opioids and clonidine. In isolated cases clonidine has been administered epidurally at a dose of 1500 microg/day for almost 5 months without evidence for any histotoxic property of clonidine. Side effects often observed during administration of alpha(2)-adrenoceptor agonists are dry mouth, sedation, hypotension and bradycardia. Therapeutic interventions are usually not required.
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PMID:[Alpha 2-adrenoceptor agonists for the treatment of chronic pain]. 1279 65


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