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

Although radiotherapy is highly effective in relieving bone pain from cancer invasion, the mechanism of pain relief remains unclear. To explore the mechanism of radiotherapy-induced analgesia, we have developed an animal model of bone pain resulting from cancer invasion. Using this animal model system, radiation-induced pain response and pain-related signals in the spinal cord were analyzed. The hind paw model of bone pain from cancer invasion was developed by injecting transplantable hepatocellular carcinoma, HCa-1, into the periosteal membrane of the foot dorsum in C3H/HeJ mice. Bony invasion from HCa-1 cells was confirmed by histopathological examinations. We also measured the development of pain-associated behaviors. In this model, changes in the objective level of pain response after irradiation of the tumor were analyzed. Expression of pain-related host signals in the spinal cord, such as calcitonin gene-related peptide (CGRP), substance P, and c-fos, was investigated with immunohistochemical staining. In the histopathological examinations, bone invasion from HCa-1 cells was seen from day 7 and was evident at day 14 after injection. Measurable pain-associated behaviors were developed from day 7. In this model, mice treated with radiotherapy showed decreased objective levels of pain with a higher threshold to graded mechanical stimulation than did control mice from day 3 after irradiation. After irradiation of tumors, significant decreases in the expression of CGRP were shown in the spinal cord, whereas neither substance P nor c-fos showed any alteration. We developed a novel hind paw model of bone pain from cancer invasion that was confirmed by histopathological examination and measurable pain-associated behaviors. Radiotherapy decreased the objective level of pain and the underlying mechanism involved in the alteration of pain-related host signal, CGRP, in the spinal cord.
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PMID:Radiation-induced alteration of pain-related signals in an animal model with bone invasion from cancer. 1565 96

Substance P (SP) binding to neurokinin 1 receptors (NK1R) in the spinal cord reportedly plays an important role in the micturition reflex as well as in nociceptive responses. We therefore investigated the effect of ablation of NK1R-expressing neurons in the spinal cord using saporin, a ribosome-inactivating protein, conjugated with [Sar9, Met (O2)11]SP, a specific ligand of NK1R (SSP-saporin), on the micturition reflex in rats. In female Sprague-Dawley rats, SSP-saporin (1.0 or 1.5 microM) or saporin (1.5 microM) only was injected through an intrathecal catheter implanted at the L6-S1 level of the spinal cord. Three weeks after intrathecal administration of SSP-saporin, NK1R immunoreactivity in lamina I of the spinal cord was significantly reduced, but cystometric parameters in awake rats were not altered. Instillation of capsaicin (15 microM) into the bladder of normal rats induced bladder overactivity. This response to capsaicin was significantly suppressed in SSP-saporin-treated animals. SSP-saporin treatment also decreased c-fos expression in the dorsal horn of the spinal cord induced by instillation of capsaicin into the bladder. These data indicate that NK1R-expressing neurons in the superficial layer of the dorsal horn play an important role in transmission of nociceptive afferent information from the bladder to induce bladder overactivity and spinal c-fos expression elicited by bladder irritation. Toxin-induced damage of NK1R-expressing neurons in the lumbosacral spinal cord may provide an effective modality for treating overactivity and/or nociceptive responses in the bladder without affecting normal micturition.
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PMID:Elimination of rat spinal neurons expressing neurokinin 1 receptors reduces bladder overactivity and spinal c-fos expression induced by bladder irritation. 1569 58

Antagonists at neurokinin 1 (NK1) receptors are attracting attention as potential treatments for depressive states in light of their actions in behavioural models predictive of antidepressant properties, their modulation of corticolimbic monoaminergic transmission, and their influence upon neural plasticity. Here, we evaluated the influence of NK1 receptor blockade upon two immediate early genes, Arc and c-fos, implicated in mechanisms of synaptic plasticity. Administration of the selective NK1 receptor antagonist, GR 205,171 (40, but not 1, 5 or 10 mg/kg i.p.), elicited a pronounced elevation in mRNA encoding Arc in both outer and inner layers of the parietal cortex of rat brain. This action was region-specific inasmuch as Arc expression did not change in other cortical territories examined including frontal cortex, nor in CA1, CA3 and the dentate gyrus of the hippocampus. In comparison to GR 205,171, its less active isomer GR 226,206 (1-40 mg/kg) did not significantly modify Arc gene expression in parietal cortex or other cortical areas. GR 205,171 (40 mg/kg) also increased the abundance of c-fos mRNA in outer and inner parietal cortex and caused a corresponding increase in c-fos immunoreactivity in this region. GR 226,206 (40 mg/kg i.p.) had no effect on either c-fos mRNA or protein in parietal cortex. In conclusion, administration of GR 205,171 elicits a stereospecific increase in Arc and c-fos expression in rat parietal cortex but not in other cortical regions. These data suggest that the parietal cortex plays a role in the central actions of NK1 receptor antagonists.
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PMID:Stereoselective and region-specific induction of immediate early gene expression in rat parietal cortex by blockade of neurokinin 1 receptors. 1620 22

Behavioral studies have demonstrated that chronic food restriction augments the rewarding and motor-activating effects of centrally injected psychostimulants and direct dopamine (DA) receptor agonists. Recently, it has been shown that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958, produces an enhanced locomotor-activating effect as well as increased activation of striatal ERK 1/2 MAP kinase, CaM kinase II, CREB, and c-fos in food-restricted (FR) relative to ad libitum fed (AL) rats. Striatal neurons that express the D-1 DA receptor coexpress dynorphin and substance P, and CREB is known to couple D-1 DA receptor stimulation to preprodynorphin (ppD) gene expression. The purpose of the present study was to examine possible genomic consequences of FR using real-time quantitative RT-PCR to measure striatal neuropeptide gene expression 3 h after i.c.v. injection of SKF-82958 (20 microg). Results indicate that, in nucleus accumbens (NAc), basal levels of ppD and preprotachykinin (ppT) mRNA are lower in FR than AL rats. This may reflect a decrease in tonic DA transmission during FR which precedes the compensatory upregulation of postsynaptic D-1 DA receptor-mediated cell signaling. In response to SKF-82958 challenge, however, FR subjects displayed greater levels of ppD and ppT mRNA in NAc than did AL subjects. A similar trend was seen in caudate-putamen (CPu). SKF-82958 also increased preproenkephalin (ppE) mRNA in Nac, but not CPu, with no difference between feeding groups. The present findings regarding ppD and ppT are consistent with prior findings of increased behavioral and cellular responses to acute D-1 DA agonist challenge in FR rats. The functional consequences of increased neuropeptide gene expression in response to acute drug challenge remain to be investigated but may include modulation of behavioral effects that emerge with repeated drug exposure, including sensitization, tolerance, and addiction.
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PMID:Comparison of basal and D-1 dopamine receptor agonist-stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats. 1625 73

Psychostimulant-induced molecular changes in cortico-basal ganglia-cortical circuits play a critical role in addiction and dependence. These changes include alterations in gene regulation particularly in projection neurons of the sensorimotor striatum. We previously showed that cocaine-induced gene regulation in such neurons is dependent on the behavior performed during drug action. Rats trained on a running wheel under the influence of cocaine for 4 days subsequently displayed greater c-fos induction by cocaine than untrained controls. This effect was selective for the sensorimotor striatum, which is known to mediate forms of motor learning. In the present study, we investigated whether this enhanced cellular responsiveness was associated with learning of wheel running or with prolonged running (exercising), by assessing c-fos inducibility after 1, 2, or 8 days of training. Wheel training was performed after injection of cocaine (25 mg/kg) or vehicle, and c-fos induction by a cocaine challenge was measured 24 h later. Rats that trained under cocaine (but not vehicle) showed a greater c-fos response in the striatum compared to locked-wheel controls. This effect was present after the 1-day training, peaked after 2 days, and dissipated by 8 days of training. Similar effects were found for substance P, but not enkephalin, expression. These changes in striatal gene regulation paralleled improvement in wheel running, which was facilitated by cocaine. Thus, these training-induced molecular changes do not appear to represent exercising effects, but may reflect motor learning-associated neuronal changes altered by cocaine. Such cocaine effects may contribute to aberrant motor learning implicated in psychostimulant addiction.
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PMID:Motor-skill learning-associated gene regulation in the striatum: effects of cocaine. 1639 6

The mechanism of pancreatitis-induced pain is unknown. In other tissues, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to liberate CGRP and substance P (SP) in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain, respectively. We evaluated the contribution of TRPV1, CGRP, and SP to pancreatic pain in rats. TRPV1, CGRP, and SP were coexpressed in nerve fibers of the pancreas. Injection of the TRPV1 agonist capsaicin into the pancreatic duct induced endocytosis of the neurokinin 1 receptor in spinal neurons in the dorsal horn (T10), indicative of SP release upon stimulation of pancreatic sensory nerves. Induction of necrotizing pancreatitis by treatment with L-arginine caused a 12-fold increase in the number of spinal neurons expressing the proto-oncogene c-fos in laminae I and II of L1, suggesting activation of nociceptive pathways. L-arginine also caused a threefold increase in spontaneous abdominal contractions detected by electromyography, suggestive of referred pain. Systemic administration of the TRPV1 antagonist capsazepine inhibited c-fos expression by 2.5-fold and abdominal contractions by 4-fold. Intrathecal, but not systemic, administration of antagonists of CGRP (CGRP(8-37)) and SP (SR140333) receptors attenuated c-fos expression in spinal neurons by twofold. Thus necrotizing pancreatitis activates TRPV1 on pancreatic sensory nerves to release SP and CGRP in the dorsal horn, resulting in nociception. Antagonism of TRPV1, SP, and CGRP receptors may suppress pancreatitis pain.
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PMID:Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. 1639 78

Secondary hyperalgesia in the monoarthritic rat is accompanied by a decrease in nociceptive activation of spinal neurons expressing GABA(B) receptors and by the opposite effect in the cells expressing neurokinin 1 (NK1)-receptors. In order to ascertain the relative role of each receptor, the effects of intrathecal administration of SP-saporin (SP-SAP), baclofen or both were evaluated, using a model of secondary hyperalgesia that consists of mechanical stimulation of the hindlimb skin close to an inflamed joint. Four days after the induction of monoarthritis by intraarticular injection of Complete Freund's Adjuvant (CFA), a cannula was implanted at T(13)-L(1) level and 10 microl of saline or SP-SAP (10(-6) M) were intrathecally (i.t.) injected. Fourteen days after CFA-injection, half of the animals from each group received i.t. injections of 10 microl saline and the remainder were injected with the same volume of baclofen (1 microg). Ten minutes later, the animals were behaviorally evaluated by the von Frey test or submitted to noxious mechanical stimulation to analyze c-fos expression. The von Frey thresholds increased after the treatments, but more pronouncedly after baclofen or SP-SAP plus baclofen. In segments L(2)-L(3), the spinal area that receives input from the stimulated skin close to the inflamed joint, the numbers of Fos-immunoreactive neurons were reduced after the three treatments both in the superficial and deep dorsal horn. In segments T(13)-L(1), the numbers of Fos-immunoreactive neurons were significantly reduced after treatment with SP-SAP plus baclofen in both dorsal horn regions, and in the deep dorsal horn after baclofen treatment. We conclude that both GABA(B) and NK1 receptors of spinal dorsal horn neurons participate in secondary hyperalgesia in the monoarthritic rat, although the decrease in GABA inhibition appears to play a more important role than the increase in SP-mediated effects.
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PMID:Secondary hyperalgesia in the monoarthritic rat is mediated by GABAB and NK1 receptors of spinal dorsal horn neurons: a behavior and c-fos study. 1680 1

The efficacy of electroacupuncture (EA) for treating patients with diarrhea-predominant IBS has been confirmed in the authors' former research, but the regulatory mechanism of EA in IBS is still unknown. The aim of this study was to explore the relationship between the effect of EA on treating IBS rats and the activation and proliferation of mast cell (MC), the secretion of substance P(SP), and vasoactive intestinal polypeptide (VIP). The IBS rat model was set up with stress of binding limbs and colorectal distention. All rats were randomly assigned to four groups (Normal, Model, Tegaserod and EA). Hematoxylin and eosin staining has been used to observe the pathological change in the rats' colonic mucosa and an AWR scoring system has been applied to evaluate improvement of visceral hypersensitivity in various methods of the different groups. Toluidine blue improved method (TBI) and immunohistochemistry have also been involved in observations of mucous mast cells in the colon, change of c-fos positive cells, and secretion of SP, SPR, VIP, VIPR in the local colon. Firstly, the threshold of visceral sensitivity in the rats model with IBS was remarkably reduced (P < 0.01). The MC count in colonic mucosa and c-fos positive cells count increased significantly (P < 0.01) with positive correlation within each. Secondly, EA on ST-25 and Tegaserod pouring into the stomach can inhibit the proliferation and activation of MC in the colon and regulate secretion of SP, SPR, VIP, VIPR (P < 0.01, P < 0.05), while the effect of EA is obviously superior to Tegaserod. We concluded, firstly, that the abnormal proliferation and activation of mucous mast cells in the colon, and oversecretion of neuropeptides such as SP, VIP and their receptors could be one of key mechanisms of etiology of IBS. Secondly, the inhibition of activation and proliferation and the secretion of SP, VIP could be major effects of EA when treating rats with IBS.
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PMID:Regulatory mechanism of electroacupuncture in irritable bowel syndrome: preventing MC activation and decreasing SP VIP secretion. 1799 87

Neurogenic inflammatory responses have recently been linked to both acute and chronic pathological conditions in the urinary tract. Neurogenic inflammation encompasses a series of vascular and non-vascular inflammatory responses, triggered by the activation of primary sensory neurons and the subsequent release of inflammatory neuropeptides, including substance P and calcitonin gene-related peptide. The reduction of neurogenic inflammatory responses may be key in the mode of action of the adrenergic alpha(1)-adrenoceptor antagonists used to treat lower urinary tract symptoms (LUTS). Indeed, the alpha(1)-adrenoceptor antagonist alfuzosin inhibits expression of the oncogene c-fos- a marker of nociceptive pathway activation - evoked by cyclophosphamide in rats. Capsaicin ameliorates urinary bladder symptoms through its stimulatory action on the transient receptor potential vanilloid 1 (TRPV1) calcium channel, resulting in desensitization of bladder sensory nerve terminals. Involvement of the TRP cation channel, subfamily A, member 1 (TRPA1) has also been reported in models of neurogenic inflammation and nociception promoted by the cyclophosphamide metabolite, acrolein. Blockade by alfuzosin demonstrates the beneficial effects of alpha(1)-adrenoceptor antagonists on neurogenic inflammation via the transient receptor potential family of ionic channels. Consequently, these drugs may have an important role in reducing LUTS.
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PMID:The concept of neurogenic inflammation. 1830 78

Vinpocetine, a derivative of vincamine, widely used in the clinical pharmacotherapy of cerebral circulatory diseases, inhibits retrograde axoplasmic transport of nerve growth factor (NGF) in the peripheral nerve, resulting in transganglionic degenerative atrophy (TDA) in the related ipsilateral superficial spinal dorsal horn, as shown in our previous publications. TDA induced by vinpocetine has been demonstrated to be followed by depletion of the marker enzyme fluoride-resistant acid phosphatase (FRAP) and its isoenzyme thiamine monophosphatase (TMP), and by the decrease in the pain-related neuropeptide substance P from laminae I-II-(III) from the segmentally related, ipsilateral substance of Rolando of the spinal cord. In the present paper, we report on the behavioral effects of perineurally administered vinpocetine. Nociception, induced by intraplantar injection of formalin, was mitigated by vinpocetine; increased expression of c-fos in the ipsilateral, segmentally related upper dorsal horn was also prevented. Since vinpocetine is not a microtubule inhibitor, and its chemical structure differs from that of vincristin and vinblastin (used formerly by us in the therapy of intractable, chronic neuropathic pain), its mode of action is enigmatic. We assume that the effect of vinpocetine in blocking retrograde axoplasmic transport of NGF might be related to its interaction with membrane trafficking proteins, such as signalling endosomes and the endocytosis-mediating "pincher" protein. Temporary, locally restricted decrease of nociception, induced by vinpocetine, might be useful in the clinical treatment of intractable, chronic neuropathic pain, since vinpocetine can successfully be applied by transcutaneous iontophoresis.
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PMID:Mitigation of nociception via transganglionic degenerative atrophy: possible mechanism of vinpocetine-induced blockade of retrograde axoplasmic transport. 1841 67


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