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 time course of histochemical changes in the dorsal horn of rats subjected to an experimental peripheral neuropathy has been examined. Qualitative and quantitative analyses of the changes in dorsal horn staining were made for soybean agglutinin (SBA)-binding glycoconjugates, the soluble lectins RL-14.5 and RL-29, the growth-associated protein (GAP)-43, and the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). These analyses were made at various time points after chronic constriction of the sciatic nerve. Quantitative analysis indicated that staining density increased in the normal territories stained for SBA-binding glycoconjugates, RL-14.5, RL-29, and GAP-43 on the neuropathic side compared with the control side. In addition, there was an extension of the territories stained for SBA-binding glycoconjugates and RL-29 ipsilateral to the injury. The peak increases occurred at 14 or 28 days, followed by a decrease toward control levels by 70 days. In contrast, the staining density for SP in the ipsilateral dorsal horn decreased at 3 and 5 days and reached a peak decrease at 14 days. Then, the staining for SP returned toward control values. The staining for CGRP was unchanged at all time points examined. Dorsal rhizotomies ipsilateral to the nerve injury in neuropathic rats indicated that the increases in staining were attributable to changes in primary afferent neurons. These data suggest that peripheral neuropathy causes complex degenerative and regenerative changes in the central branches of primary afferent neurons. The associated synaptic reorganization may contribute to the sensory abnormalities that accompany peripheral neuropathy.
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PMID:Time course of degenerative and regenerative changes in the dorsal horn in a rat model of peripheral neuropathy. 906 34

Understanding pain or, more precisely, the different types of pain, is above all a question of understanding its physiological mechanisms and, in this regard, the role of basic research has without doubt been to trigger the development of new therapeutic strategies. In an approach to these problems, the main international teams involved in pain research have attempted to develop models of experimental pain in rats. Clearly, research aimed at developing these models is controlled by certain ethical considerations; however, in this context, the end must surely justify the means. The main models used (acute or chronic inflammation, rheumatoid arthritis, peripheral neuropathy) certainly do not give a comprehensive representation of all the pain syndromes encountered in clinical practice, but they do provide new data concerning the physiological, behavioural and pharmacological aspects of pain. While giving a brief description of the complexity of the pain circuit, this article also makes reference to certain pharmacological approaches to the treatment of pain. Peripheral nociceptive messages are conveyed by a mosaic of unmyelinated free fibres distributed throughout cutaneous, muscular and articular tissue, and within the visceral walls. They are then transmitted via various nerve endings (polymodal nociceptors) by small diameter A delta and C fibres, which are activated by mechanical, thermal and chemical stimuli. It is nevertheless difficult to ascertain whether these small diameter fibres are involved only in nociception (specific nociceptors) or whether pain causes an excessive activation of these receptors, which under normal conditions have a role in the reflex that regulates various functions (nonspecific nociceptors). Numerous chemical substances play a part in generating nociceptive impulses (e.g. histamine, serotonin, prostaglandins). Furthermore, the role of neuropeptides, such as calcitonin gene-related peptide and particularly substance P, has been clearly demonstrated in the activation of early neurogenic inflammation. Other substances, such as bradykinin and cytokines, are involved in prolonging the sensation of pain. Nerve growth factor also prolongs the sensation of pain by increasing the cellular excitability of nociceptors and promoting the action of the sympathetic nervous system, which has a major role in controlling pain. The very great diversity of all these interacting substances makes the pharmacological treatment of pain extremely complex. Nevertheless, new therapeutic advances are providing interesting approaches, particularly the development of specific inhibitors of cyclo-oxygenase 2 (COX 2), which is produced by the inflammatory process. Such inhibitors would preserve COX 1, which is both constitutive and physiological, and thereby provide improved tolerability compared with currently used NSAIDs, which act upon both COX pathways. A major focus of research relating to new analgesics is the development of synthetic antagonists of bradykinin, substance P and N-methyl-D-aspartate receptors. An improved understanding of anatomical and electrophysiological processes has led to the discovery of new ascending pathways that transmit nociceptive messages to the reticular formation, the hypothalamus, and the amygdala, as well as to certain areas of the cortex. As a result the notion of one single pain centre is no longer valid. This idea is further reinforced by the knowledge that, at different stages of the pain pathway, different control systems constantly modulate the transmission of nociceptive information. Consequently, at a spinal level, activation of the large diameter cutaneous fibres (A alpha et beta) blocks pain stimuli transmitted by the small diameter fibres. Knowledge of this "gate control' mechanism of the posterior horn of the spinal cord is put to practical application in treatments involving transcutaneous electrical nerve stimulation. (ABSTRACT TRUNCATED)
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PMID:[The complexity of physiopharmacologic aspects of pain]. 919 Mar 19

Quantitative receptor autoradiography was used to evaluate potential alterations in substance P (SP) and calcitonin gene-related peptide (CGRP) binding in the L4 spinal segment of rats following unilateral poisoning of the sciatic nerve with pronase. Ten days after pronase-induced deafferentation there was a significant increase in SP and CGRP binding in the superficial (I-II) and deeper (II-IV) laminae of the dorsal horn ipsilaterally. Densitometric measurements revealed a 50% return towards normal values for SP binding by 90 days postpronase injection in all laminae examined, while the density of CGRP binding showed a partial return towards normal values for laminae III-IV only. These differential responses may be indicative of the mechanisms underlying pronase-induced peripheral neuropathy.
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PMID:Changes in substance P and calcitonin gene-related peptide binding in the dorsal horn of rat spinal cord following pronase-induced deafferentation. 1035 81

Various hypotheses have been proposed to account for the mechanical hyperalgesia and spontaneous pain seen in animal models of peripheral neuropathy. The purpose of the present study was to determine whether there exists a spinal neuronal correlate to these properties. An experimental neuropathy was induced in male Sprague-Dawley rats by placing a 2-mm PE-90 polyethylene cuff around the sciatic nerve. All rats were subsequently confirmed to exhibit mechanical allodynia in the von Frey test. After induction of anaesthesia with pentobarbital and acute spinalization at T9, electrophysiological experiments were performed, recording extracellular single unit activity from ipsi- and contralateral wide dynamic range dorsal horn neurons in spinal segments L1-4. On-going activity was greater in short-term (11-22 days after cuff implantation) and long-term (42-52 days) cuff-implanted rats; 38 spikes/s in short-term versus 19 spikes/s in controls; 29 spikes/s in long-term ipsi- and contralateral neurons. Receptive fields in controls were always restricted, but in almost all cuff-implanted rats extended over the whole hind paw. Responses to noxious mechanical (pinch) and noxious heat stimulation of the cutaneous receptive field in controls consisted of the typical fast initial discharge followed by an afterdischarge. In all neurons from cuff-implanted rats the initial discharge resembled that in controls. However, the afterdischarge, particularly that in response to noxious pinch, was markedly greater in both magnitude and duration. It is suggested that the greater on-going discharge is the cellular correlate of spontaneous pain, and the potentiation of the afterdischarge in response to noxious stimulation is the correlate of hyperalgesia. Given that acutely spinalized rats were tested, only peripheral and/or spinal mechanisms can be considered to explain these data. Considering all the data, it can be concluded that there is a greater change in fibres mediating noxious mechanical than noxious thermal inputs. Among different hypotheses, the one with which the present data are most compatible is that which proposes that chronic nerve injury or inflammation induces phenotypic changes predominantly in myelinated afferents. There may be a redistribution of membrane-bound ion channels, predominantly sodium channels, which leads to ectopic activity and thus spontaneous discharge of dorsal horn neurons. With regard to mechanical stimulation-evoked synaptic input, the central terminals of myelinated afferents expand into regions of the spinal cord which normally receive their predominant input from unmyelinated nociceptive afferents. This may be coupled with a change in these myelinated afferents so that they now synthesize and release peptides, primarily substance P, from their central terminals with the result that the effects of their chemical mediators of synaptic transmission add to the effects of nociceptive inputs leading to exaggerated responses to painful stimuli, thus the basis of clinical hyperalgesia.
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PMID:Cellular mechanisms of hyperalgesia and spontaneous pain in a spinalized rat model of peripheral neuropathy: changes in myelinated afferent inputs implicated. 1088 40

We investigated the effect of topical application of capsaicin cream on withdrawal latency in the hind foot of rat in response to radiant heat in an experimental model of neuropathic pain. A neuropathic state was induced by loose ligation of the sciatic nerve with chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulus applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level by 35 days after surgery. Capsaicin cream applied to both the bilateral hind instep and sole once a day for a continuous period of 2 weeks or 4 weeks alleviated thermal hyperalgesia in a dose-dependent manner. A remarkable effect was observed 2 weeks after the start of the application and this effect proved to be reversible. On the other hand, in sham-operated animals when capsaicin cream was applied once daily from day 7 after the sham operation, from 1 day through 3 weeks following capsaicin application, withdrawal latency of the sham-operated paws of the capsaicin-treated group was significantly increased as compared to that of the vehicle cream-treated group. The effects of antagonists of glutamate receptor and tachykinin receptors were investigated 7 days post surgery. Pretreatment with MK-801 (0.5 mg kg(-1), i.p.), but not with CNQX (0.5 mg kg(-1), i.p.), reversed the thermal hyperalgesia following nerve injury. Neither of RP67580 (1--10 mg kg(-1), i.p.) nor SR48968 (1--10 mg kg(-1), i.p.) had any effect on the withdrawal latency in the injured and non-injured hind paw. These results suggest that although the manifestation of effectiveness may be delayed by changes in networks of neurotransmitters related to the nociceptive pathways following nerve injury, longer-term repetitive application of capsaicin cream has a significant therapeutic effect on subjects with painful peripheral neuropathy.
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PMID:Influence of capsaicin cream in rats with peripheral neuropathy. 1151 59

Cutaneous sensory nerves mediate inflammation and wound healing by releasing neuropeptides, such as substance P, which stimulates pro-inflammatory responses by keratinocytes, fibroblasts, and endothelial cells. The cell surface enzyme, neutral endopeptidase, degrades substance P, thereby regulating its biologic actions. We hypothesized that neutral endopeptidase enzymatic activity is increased in chronic wounds and skin from subjects with diabetes. We compared cutaneous neutral endopeptidase expression and enzymatic activity between normal controls and diabetic subjects with neuropathy and chronic wounds. Skin samples from subjects with diabetes were taken at the time of amputation for nonhealing ulcers. Skin taken from the ulcer margin, 1 cm from the ulcer (adjacent), and from the most proximal region of the amputated leg were studied. Skin biopsies from the leg of healthy control subjects were also studied. Neutral endopeptidase was localized by immunohistochemistry in all tissue sections. Neutral endopeptidase activity was measured using a fluorimetric assay. The median neutral endopeptidase activity of the ulcer margin was 1.21 x higher (p>0.2) than adjacent skin, 5.26 (p<0.001) than proximal skin, and 15.22 x higher (p<0.001) than control skin. Adjacent skin had a median neutral endopeptidase activity 4.34 x higher (p<0.001) than proximal skin and 12.58 x higher (p<0.001) than control skin. The median neutral endopeptidase activity of proximal skin was 2.90 x higher (p<0.001) than control skin. This elevated neutral endopeptidase activity in the skin and chronic ulcers of subjects with diabetes combined with peripheral neuropathy may contribute to deficient neuroinflammatory signaling and may impair wound healing in subjects with diabetes.
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PMID:Neutral endopeptidase activity is increased in the skin of subjects with diabetic ulcers. 1248 46

In this study, we examined the effect BRX-220, a co-inducer of heat shock proteins, in injury-induced peripheral neuropathy. Following sciatic nerve injury in adult rats and treatment with BRX-220, the following features of the sensory system were studied: (a) expression of calcitonin gene-related peptide (CGRP); (b) binding of isolectin B4 (IB4) in dorsal root ganglia (DRG) and spinal cord; (c) stimulation-evoked release of substance P (SP) in an in vitro spinal cord preparation and (d) nociceptive responses of partially denervated rats. BRX-220 partially reverses axotomy-induced changes in the sensory system. In vehicle-treated rats there is a decrease in IB4 binding and CGRP expression in injured neurones, while in BRX-220-treated rats these markers were better preserved. Thus, 7.0 +/- 0.6% of injured DRG neurones bound IB4 in vehicle-treated rats compared to 14.4 +/- 0.9% in BRX-220-treated animals. Similarly, 4.5 +/- 0.5% of DRG neurones expressed CGRP in the vehicle-treated group, whereas 9.0 +/- 0.3% were positive in the BRX-220-treated group. BRX-220 also partially restored SP release from spinal cord sections to electrical stimulation of primary sensory neurones. Behavioural tests carried out on partially denervated animals showed that BRX-220 treatment did not prevent the emergence of mechanical or thermal hyperalgesia. However, oral treatment for 4 weeks lead to reduced pain-related behaviour suggesting either slowly developing analgesic actions or enhancement of recovery processes. Thus, the morphological improvement seen in sensory neurone markers was accompanied by restored functional activity. Therefore, treatment with BRX-220 promotes restoration of morphological and functional properties in the sensory system following peripheral nerve injury.
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PMID:The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury. 1476 55

Peripheral nerve injury in humans can produce a persistent pain state characterized by spontaneous pain and painful responses to normally innocuous stimuli (allodynia). Here we attempt to identify some of the neurophysiological and neurochemical mechanisms underlying neuropathic pain using an animal model of peripheral neuropathy induced in male Sprague-Dawley rats by placing a 2-mm polyethylene cuff around the left sciatic nerve according to the method of Mosconi and Kruger. von Frey hair testing confirmed tactile allodynia in all cuff-implanted rats before electrophysiological testing. Rats were anesthetized and spinalized for extracellular recording from single spinal wide dynamic range neurons (L(3-4)). In neuropathic rats (days 11-14 and 42-52 after cuff implantation), ongoing discharge was greater and hind paw receptive field size was expanded compared to control rats. Activation of low-threshold sensory afferents by innocuous mechanical stimulation (0.2 N for 3 s) in the hind paw receptive field evoked the typical brief excitation in control rats. However, in neuropathic rats, innocuous stimulation also induced a nociceptive-like afterdischarge that persisted 2-3 min. This afterdischarge was never observed in control rats, and, in this model, is the distinguishing feature of the spinal neural correlate of tactile allodynia. Electrical stimulation of the sciatic nerve at 4 and at 20 Hz each produced an initial discharge that was identical in control and in neuropathic rats. This stimulation also produced an afterdischarge that was similar at the two frequencies in control rats. However, in neuropathic rats, the afterdischarge produced by 20-Hz stimulation was greater than that produced by 4-Hz stimulation. Given that acutely spinalized rats were studied, only peripheral and/or spinal mechanisms can account for the data obtained; as synaptic responses from C fibers begin to fail above approximately 5-Hz stimulation [Pain 46 (1991) 327], the afterdischarge in response to 20-Hz stimulation suggests a change mainly in myelinated afferents and a predominant role of these fibers in eliciting this afterdischarge. These data are consistent with the suggestion that peripheral neuropathy induces phenotypic changes predominantly in myelinated afferents, the sensory neurons that normally respond to mechanical stimulation. The NK-1 receptor antagonist, CP-99,994 (0.5 mg/kg, i.v.), depressed the innocuous pressure-evoked afterdischarge but not the brief initial discharge of wide dynamic range neurons, and decreased the elevated ongoing rate of discharge in neuropathic rats. These results support the concept that following peripheral neuropathy, myelinated afferents may now synthesize and release substance P. A result of this is that tonic release of substance P from the central terminals of these phenotypically altered neurons would lead to ongoing excitation of NK-1-expressing nociceptive spinal neurons. In addition, these spinal neurons would also exhibit exaggerated responses to innocuous pressure stimulation. The data in this study put forth a possible neurophysiological and neurochemical basis of neuropathic pain and identify substance P and the NK-1 receptor as potential neurochemical targets for its management.
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PMID:Nociceptive response to innocuous mechanical stimulation is mediated via myelinated afferents and NK-1 receptor activation in a rat model of neuropathic pain. 1502 55

We have previously demonstrated that Goto-Kakizaki (GK) rats with spontaneous type-2 diabetes and peripheral neuropathy exhibit regional osteopathic changes. In the present study on 18 GK rats and 21 control Wistar rats, the occurrence of the sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), and the autonomic neuropeptide Y (NPY) was analysed in bone and joints, dorsal root ganglia and lumbar spinal cord by immunohistochemistry and radioimmunoassay (RIA). Immunohistochemistry disclosed a predominance of immunoreactivities in vessel-related nerve fibers, although some were also seen in free terminals. While SP, CGRP and NPY in periosteum, cortical bone and synovium was confined to neuronal tissue, the bone marrow in addition exhibited an abundance of NPY-positive megakaryocytes. Apart from this cellular source of NPY, the observations suggest that the three neuropeptides analysed in bone and joints are of neuronal origin. Quantification by RIA showed a significant decrease of NPY in cortical bone (-36%), bone marrow (-66%) and ankle (-29%) of GK rats. CGRP was decreased in the spinal cord (-19%) and dorsal root ganglia (-26%) but was unchanged in bone and joints, as with SP. Given the suggested anabolic role of NPY and CGRP on bone, neuropeptidergic deficit in diabetes may prove to be an important factor underlying the development of regional osteopenia.
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PMID:Bone and joint neuropathy in rats with type-2 diabetes. 1509 98

Xeroderma pigmentosum group A (XPA) is a hereditary disorder characterized by cutaneous symptoms and progressive neurodegeneration. Since XPA patients exhibit peripheral neuropathy, neuronal deafness, rigidity, dysphagia, and laryngeal dystonia, it is indispensable for investigation of the neurodegeneration to analyze brainstem and basal ganglia lesions clinically and pathologically; we have previously shown the role of oxidative stress in the development of basal ganglia lesions. Here we immunohistochemically examined the expression of neurotransmitters, calcium-binding proteins, and neuropeptides in the brainstem, basal ganglia, and thalamus in 5 XPA autopsy cases. In the brainstem, immunoreactivity for tyrosine hydroxylase, tryptophan hydroxylase, and calbindin-D28K was severely reduced throughout the brainstem in all the XPA cases. Nevertheless, the expressions of parvalbumin, substance P, and methionine-enkephalin in the brainstem were comparatively preserved; the exception being reduced immunoreactivity for them in the cochlear and dorsal column nuclei in 3 cases. The large cell neurons in the putamen were preferentially reduced, the immunoreactivity for tyrosine hydroxylase reflecting the dopaminergic afferent and efferent pathways was severely affected, and the expression of 3 calcium binding proteins (i.e. parvalbumin, calbindin-D28K, and calretinin) was disturbed in various ways. The expression of substance P and methionine-enkephalin, which are involved in the efferent pathways in the basal ganglia, in the globus pallidus and substantia nigra was spared. It is speculated that the selective damage to the dopamine system in the basal ganglia and the disturbed monoaminergic expression in the brainstem could be related to clinical abnormalities such as the rigidity, laryngeal dystonia, and several neurophysiological changes. Functional analysis of autopsy brains will facilitate clarification of the pathogenesis of the neurodegeneration in XPA.
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PMID:Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. 1553 32


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