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)

Increased pain fibre activity in response to tissue injury results in changes in gene expression, and prolonged changes in nerves and their environment. The resulting hyperalgesia and prolonged spontaneous pain are due both to increased sensitivity of peripheral nociceptors (primary hyperalgesia) and to facilitated spinal cord transmission (secondary hyperalgesia, receptive field expansion and allodynia). Hyperexcitability of dorsal horn neurones is first triggered by increased neuronal barrage into the central nervous system ('wind-up'), and later by retrograde chemical influences from the peripheral inflammation (central sensitisation). Central transmission and hyperexcitability are mediated by excitatory amino acids (aspartate and glutamate) and by tachykinins (substance P). Normally, the net effect of the activity in a complex network of inhibitory neurones in the spinal cord ('gate control'), driven by descending projections from brain stem sites, is to dampen and counteract the spinal cord hyperexcitability produced by tissue or nerve injury. Thus, peripherally evoked pain impulses pass through a filtering process involving gamma-aminobutyric acid, glycine and enkephalins. The activity of these substances in the spinal cord usually attenuates and limits the duration of pain. In the case of persistent pain, there is evidence of pathological reduction of the supraspinal net inhibitory actions in combination with ectopic afferent input in damaged nerves. Hence, the pathology of chronic pain (neuropathic pain) differs from that of nociceptive pain, and conventional pharmacological treatment of chronic central pain is usually less successful than treatment of inflammation-related pain. The many newly discovered mechanisms for the transmission and modulation of pain impulses are characterised by complex activity-dependent plasticity, which means that therapeutic strategies for persistent pain must be adapted to changing targets--either at the site of injury or at other sites in the central nervous system.
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PMID:[A breakthrough in the research on pain. Survey of the synaptic network may result in new analgesics]. 942 46

We have used a partial sciatic nerve ligation model to examine the time course for changes in the expression of mRNA for three peptides related to pain transmission at spinal sites (dynorphin, enkephalin and substance P), during the development of allodynia. Enhanced expression of mRNA for dynorphin and substance P was observed in the dorsal horn on the same side as the partial nerve ligation. Increased expression of dynorphin mRNA was biphasic. The initial increases in expression of dynorphin mRNA occurred at 3 h, and a secondary peak was observed 1-3 days after surgery. The secondary increases coincided roughly with increased substance P mRNA expression. However, both dynorphin and substance P mRNA returned to control values after 1 week despite continuing allodynia. No significant changes in expression of mRNA for enkephalin were observed. The elevation of substance P mRNA in intrinsic spinal cord neurons may be secondary to changes in immediate early genes c-fos and jun-B, whereas the expression of dynorphin and enkephalin mRNA is differently regulated. The results also suggest that changes in the expression of the three neuropeptides are not critically involved in the development and maintenance of chronic pain or allodynia.
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PMID:Temporal changes in spinal cord expression of mRNA for substance P, dynorphin and enkephalin in a model of chronic pain. 942 59

Increased pain fibre activity in response to tissue injury results in changes in gene expression and prolonged changes in nerves and their environment. The resulting hyperalgesia and prolonged spontaneous pain are due both to increased sensitivity of peripheral nociceptors (primary hyperalgesia) and to faciliated spinal cord transmission (secondary hyperalgesia, receptive field expansion and allodynia). Hyperexcitability of dorsal horn neurones is first triggered by increased neuronal barrage into the central nervous system ("wind-up"), and later by retrograde chemical influences from the peripheral inflammation (central sensitisation). Central transmission and hyperexcitability are mediated by excitatory amino acids (aspartate and glutamate) and by tachykinins (substance P). Normally, the net effect of the activity in a complex network of inhibitory neurones in the spinal cord ("gate control"), driven by descending projections from brain stem sites, is to dampen and counteract the spinal cord hyperexcitability produced by tissue or nerve injury. Thus, peripherally evoked pain impulses pass through a filtering process involving gamma-aminobutyric acid, glycine and enkephalins. The activity of these substances in the spinal cord usually attenuates and limits the duration of pain. In the case of persistent pain, there is evidence of pathological reduction of the supraspinal net inhibitory actions in combination with ectopic afferent input in damaged nerves. Hence, the pathology of chronic pain (neuropathic pain) differs from that of nociceptive pain and conventional pharmacological treatment of chronic central pain is usually less successful than treatment of inflammation-related pain. The many newly discovered mechanisms for the transmission and modulation of pain impulses are characterised by complex activity-dependent plasticity, which means that therapeutic strategies for persistent pain must be adapted to changing targets--either at the site of injury or at other sites in the central nervous system.
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PMID:[Breakthrough in pain research. Charting of the synaptic network may lead to new analgesics]. 946

Sensitization is manifested as an increased response of neurones to a variety of inputs following intense or noxious stimuli. It is one of the simplest forms of learning and synaptic plasticity and it represents an important feature of nociception. In the spinal cord, repeated stimulation (at constant strength) of dorsal root afferents including nociceptive C fibres can elicit a progressive increase in the number of action potentials generated by motoneurones and interneurones. This phenomenon is termed "action potential windup" and is used as a cellular model of pain sensitization developing at the level of the central nervous system. Understanding the mechanisms responsible for windup generation might allow clarification of the cellular mechanisms of pain signalling and development of new strategies for pain treatment. Action potential windup is observed in a minority of cells only, indicating that certain cell-specific mechanisms are responsible for its generation. The most reliable index to predict windup generation is the rate at which the membrane potential is depolarized during repetitive stimulation. This phenomenon has been proposed to be due to gradual recruitment of NMDA receptor activity, to summation of slow excitatory potentials mediated by substance P (and related peptides) or to facilitation of slow calcium channels by metabotropic glutamate receptors. Little is known about the role of synaptic inhibition in windup, although it should not be underestimated. Each theory per se is unable to account for all the experimental observations. Since NMDA receptors are involved in many forms of synaptic plasticity, additional mechanisms such as summation of slow peptidergic potentials, facilitation of slow Ca2+ currents and disinhibition are proposed as necessary to impart specificity to pain-induced sensitization. These additional mechanisms might be species specific and change during development or chronic pain states.
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PMID:Sensitization of pain pathways in the spinal cord: cellular mechanisms. 948 3

The lack of objective parameters makes the measurement of pain and the efficacy of pain treatment in patients with chronic pain very difficult. We performed acupuncture therapy in fibromyalgia patients and established a combination of methods to objectify pain measurement before and after therapy. The parameters corresponded to patients' self-report. Twenty-nine fibromyalgia patients as defined by ACR-criteria (25 women, 4 men) with a mean age of 48.2 +/- 2.0 years and a mean disease duration of 6.1 +/- 1.0 years participated in the study. Pain levels and positive tender points were assessed using the visual analogue scale (VAS, i.e., range 0-100 mm) and dolorimetry. Serotonin and substance P levels in serum and the serotonin concentration in platelets were measured concomitantly. During acupuncture therapy no analgesic medication was allowed. The VAS scores decreased from 64.0 +/- 3.4 mm before therapy to 34.5 +/- 4.3 mm after therapy (P < 0.001). Dolorimetry revealed a decreased number of tender points after therapy from 16.0 +/- 0.6 to 11.8 +/- 1.0, P < 0.01. Serotonin levels decreased from 715.8 +/- 225.8 micrograms/10(12) platelets to 352.4 +/- 47.9 micrograms/10(12) platelets (P < 0.01), whereas the serum concentration increased from 134.0 +/- 14.3 ng/ml to 171.2 +/- 14.6 ng/ml (P < 0.01). Substance P levels in serum increased from 43.4 +/- 3.5 pg/ml to 66.9 +/- 8.8 pg/ml (P < 0.01). Acupuncture treatment of patients with fibromyalgia was associated with decreased pain levels and fewer positive tender points as measured by VAS and dolorimetry. This was accompanied by decreased serotonin concentration in platelets and an increase of serotonin and substance P levels in serum. These results suggest that acupuncture therapy is associated with changes in the concentrations of pain-modulating substances in serum. The preliminary results are objective parameters for acupuncture efficacy in patients with fibromyalgia.
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PMID:Pain treatment of fibromyalgia by acupuncture. 967 97

The mechanism mediating the chronic pain associated with lumbar disc degeneration may involve neurotransmitters elaborated by dorsal root ganglion (DRG). This hypothesis has been tested in an applicable rabbit model of disc degeneration. Twenty control male rabbits underwent a soft-tissue release; 20 experimental rabbits sustained a facetectomy and capsulotomy and received an acute torsional lumbar injury. The levels of calcitonin gene-related peptide, vasoactive intestinal peptide, and substance P were measured in the DRG, spinal cord, and disc at 10, 30, 60, and 90 days postoperatively. Torsional injury was associated with a statistically significant increase in most DRG and spinal cord neurotransmitter values after 60-90 days. These points in time marked the periods of maximum biomechanical instability and disc narrowing. Such data support concepts about the association between chronic lumbar spinal instability, disc degeneration, and pain.
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PMID:Torsional injury resulting in disc degeneration in the rabbit: II. Associative changes in dorsal root ganglion and spinal cord neurotransmitter production. 972 1

The tachykinins substance P (SP) and neurokinin A, released by the C-type primary afferent fibre terminals of the small dorsal root ganglion (DRG) neurons, play important roles in spinal nociception. By means of non-radioactive in situ hybridization and whole-cell recording, we showed that the small rat DRG neurons also express the NK-1 tachykinin receptor. In situ hybridization demonstrated that the positive neurons in rat DRG sections were mainly small cells (85.9%) with diameters less than 25 microm. The remaining positive neurons (14.1%) were cells with medium diameters between 26 and 40 microm. No positive large neurons (diameters > 40 microm) were observed. Expression in small DRG neurons (diameter < 21 microm) was confirmed by in situ hybridization of isolated cells, which were demonstrated to express NK-1 receptor mRNA at a very high frequency (> 90% of small DRG neurons) and therefore were subjected to whole-cell recording. In 57 of 61 cells recorded, SP or the selective NK-1 receptor agonist [Sar9, Met(O2)11]SP (Sar-SP, 1 or 2 microM) produced a delayed vibrating inward current (50-300 nA) with a long duration of 0.5-2 h. These currents were blocked by co-application of the NK-1 receptor antagonist L-668, 169 (1 microM), but were not affected by the NK-2 antagonist L-659, 877 (2 microM). Both current-clamp recording and cell-attached single-channel recording demonstrated that the long-lasting response was due to the opening of a channel with an inward current. Employment of non-Ca2+ and Ca2+ + choline solutions revealed that this channel might be a Ca2+-permeable, non-selective cation channel. The prolonged NK-1 tachykinin response exhibited extreme desensitization. This work suggests that presynaptic NK-1 autoreceptors may be present on the primary afferent terminals in the spinal cord, where they could contribute to the chronic pain and hyperalgesia.
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PMID:Small sensory neurons in the rat dorsal root ganglia express functional NK-1 tachykinin receptor. 974 83

Clinical and animal studies were performed to evaluate the effect of repeated transcutaneous electric nerve stimulation (TENS) applied on acupoints of pain patients and the effect of repeated electroacupuncture (EA) at acupoints of the rat on experimental arthritic pain models. Attempts were also made to evaluate whether substance P (SP), cholecystokinin octopeptide (CCK-8), and met5-enkephalin (MEK) are involved in the mechanism of the cumulative effect of repeated EA on experimental arthritis using neuropharmacological (receptor antagonists) and neurochemical (radioimmunoassay, RIA) approach. The main results show that repeated TENS of 100 Hz relieves spinal spasticity in a cumulative manner, while TENS of 2/15 Hz is effective in relieving chronic pain. In animal chronic pain models, repeated EA suppressed the hyperalgesia in arthritic rats in a cumulative manner. Further studies revealed that in pain patients there was a plastic change in the release and metabolic rate of spinal opioid peptides. In arthritic rats there was also a change in the releasing rate of spinal SP, CCK-8, and MEK as compared to control rats, an effect modulated by repeated EA. These plastic changes occured under chronic pain condition and their modulation by repeated acupoint stimulation may explain the mechanisms of the cumulative effect of acupuncture on chronic pain.
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PMID:[A study on the cumulative effect of repeated electroacupuncture on chronic pain]. 977 64

The subacromial bursa is recognized as a site associated with the shoulder pain caused by rotator cuff disease in the middle-aged and elderly. Substance P is contained in primary afferent nerves, and its quantity increases during chronic pain. The amount of substance P in the subacromial bursa of patients with rotator cuff disease was examined. Radioimmunoassay and immunohistochemistry were employed to quantify and localize substance P. The preoperative pain level was measured with a visual analogue scale with 0 as no pain, 5 as moderate, and 10 as severe. Thirty-seven patients that had undergone operation were divided into two groups: one composed of 19 patients with subacromial bursitis and a partial-thickness tear of the rotator cuff (nonperforated cuff) and the other composed of 18 patients with a full-thickness tear (perforated cuff). Subacromial bursae obtained from seven fresh cadavers with no shoulder pain before death were used as controls. The visual analogue scale showed significantly greater pain in the group with the nonperforated rotator cuff than in the group with the perforated cuff. Consistent with these results, the amount of substance P in the subacromial bursa was significantly greater in the former group than in the latter. Nerve fibers immunoreactive to substance P were localized around the vessels, with a larger number of fibers in the group with the nonperforated rotator cuff. Therefore, an increased amount of substance P in the subacromial bursa appears to correlate with the pain caused by rotator cuff disease.
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PMID:Increased substance P in subacromial bursa and shoulder pain in rotator cuff diseases. 982 Feb 87

Substance P (SP) plays a central role in the transduction of second messenger signals from primary afferent nociceptive terminals to second-order neurons in the spinal cord. We have tested a recombinant engineered diphtheria toxin/SP fusion protein (DAB389SP) in acute and chronic pain models in the rat. DAB389SP binds to the SP receptor (SPR) and is internalized and kills SPR-expressing cells by blocking cellular protein synthesis. DAB389SP delivery was by intrathecal infusion, of varying duration, at the lumbar level. In the chronic constriction injury model of neuropathic pain a significant reduction in mechanically induced hyperalgesia was obtained. This effect was less marked in an acute carageenan inflammation model. Although other pain characteristics (mechano-allodynia, cold-allodynia, and heat-hyperalgesia) showed some improvement, these were less pronounced. Immunocytochemistry revealed a toxin-induced reduction in lamina I, of SPR and of NMDA NR1 subunit receptor expressing neurons, and of c-Fos, an inducible molecular marker of persistent nociceptive activity. The use of cytotoxic fusion proteins to target specific cell types may be of considerable benefit in the study of nociception and the treatment of chronic pain.
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PMID:Actions of intrathecal diphtheria toxin-substance P fusion protein on models of persistent pain. 1006 70


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