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)

While much evidence implicates substance P (SP), an endogenous neurokinin (NK), as a primary sensory transmitter of acute pain in mammalian spinal cord, its role in continuous (tonic) pain is less clear. Although glutamate is co-localized with SP in dorsal root ganglion neurons, its role in nociceptive processing is uncertain. While antagonists of NKs and excitatory amino acids (EAAs) have been found to be antinociceptive in some acute assays, they have not been tested against tonic pain. We hypothesize that: (1) NKs and EAAs contribute to signaling of tonic chemogenic nociception; and (2) interaction between NK and EAA systems is important in determining the perceived intensity of a continuous noxious stimulus. We therefore evaluated two NK antagonists ([D-Pro2,D-Trp7,9] SP (DPDT-SP, 0.26-6.6 nmoles, non-specific) and [D-Pro4, D-Trp7,9,10,Phe11]-SP(4-11) (DPDTP-octa, 1.6-12.3 nmoles, somewhat NK-1 selective], as well as DL-2-amino-5-phosphonovalerate (DL-AP5, NMDA antagonist, 0.05-1 nmole) and urethane (a kainic acid (KA) antagonist at 2.5 mumoles) for antinociceptive activity in the mouse formalin model. Administered intrathecally (i.t.), DL-AP5 and both NK antagonists were significantly antinociceptive while urethane (2.5 mumoles) and naloxone (2.7 nmoles) were inactive. A50 values for mean % analgesia, nmoles/mouse i.t. (95% CLs) were: DPDT-SP, 1.1 (0.79-1.6); DPDTP-octa, 3.9 (2.4-6.1); DL-AP5, 0.29 (0.16-0.71). The antinociception associated with 1.3 nmoles of DPDT-SP was not reversed by co-administering 2.7 nmoles of naloxone. Co-administration of 0.1 nmoles of DL-AP5 with either 1.3 nmoles of DPDT-SP or 3.3 nmoles of DPDTP-octa did not lead to additive antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model. 171 Nov 93

In the last two decades, considerable advances have been made in our understanding of the mechanisms of pain. Studies correlating subjective magnitude estimations of pain in man with activity in single nerve fibers in experimental animals, and microneurographic recordings in awake humans, have provided convincing evidence for the role of specific nociceptors and labelled lines for signalling pain sensation in the normal skin. The response properties of the different types of nociceptive afferents, both myelinated and unmyelinated, from skin, muscle, and joints make them ideal candidates for signalling pain sensations. Cutaneous inflammation from any cause results in hyperalgesia. Cutaneous hyperalgesia at the site of an injury, i.e., primary hyperalgesia, can be explained by sensitization of nociceptors. This sensitization is likely due to local release of chemical mediators in the inflamed area. The metabolites of arachidonic acid (eicasonoids) and bradykinin appear to play an important role in the sensitization of nociceptors. Similar inflammation-induced changes in response properties of fine articular afferents might explain the pain of acute arthritis. The neuropeptide substance P released from primary afferents may also play an important role in the pathogenesis of arthritis. The mechanism of hyperalgesia in the region surrounding the injury, i.e., secondary hyperalgesia, is less well understood, and probably results from changes both in the peripheral and central nervous systems. While considerable advances have been made in our understanding of the mechanisms of acute pain, the pathophysiology of most chronic pain states is still unclear. We hope that future studies in experimental animals, and careful psychophysical testing and microneurographic recordings in chronic pain patients, will lead to a better understanding of the pathophysiology of pain.
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PMID:Peripheral mechanisms of somatic pain. 328 12

Fourteen adult patients were allowed to self-administer small intravenous doses of pethidine to relieve postoperative pain. Thirteen of the patients obtained subjectively satisfactory analgesia while establishing steady-state levels of pethidine in plasma. The individual demand for pethidine was related to individual levels of fraction I endorphins and substance P-like immunoreactivity in the cerebrospinal fluid (CSF). There was a significant and inverse relationship between preoperative fraction I concentrations in CSF and the individual mean pethidine concentrations in plasma (P less than 0.05) and CSF (P less than 0.02) during self-administration. In the 24 h period encompassing surgery and postoperative self-administered analgesia, substance P decreased in 7 patients with calculated CSF pethidine great than 200 ng/ml, but remained virtually unchanged in 7 patients with calculated CSF pethidine less than 200 ng/ml. The results suggest a role for endorphins in the modulation of acute pain and are compatible with experimental evidence for an inhibitory effect of opiates on substance P release.
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PMID:Postoperative demand for analgesics in relation to individual levels of endorphins and substance P in cerebrospinal fluid. 618 55

The endorphins constitute a large family of structurally but not generically related peptides. They act pharmacologically like narcotic analgesics. An intimate connection between endorphin fibers and pain pathways is present, for instance, at the spinal level and at the first synapse of primary afferent pain fibers. These fibers may contain the neuropeptide substance P. In acute pain, naloxone injection causes a significant increase in pain suffering. A patient with high preoperative endorphin levels in the cerebrospinal fluid will require less pethidine for adequate pain relief after major abdominal surgery. Pethidine administration reduces substance P levels in the cerebrospinal fluid. The data suggest that endorphins do not have a protective role in acute pain conditions.
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PMID:Endorphins and the modulation of acute pain. 695 32

1. Monoarthritis was induced in Lewis rats by interdermal injection in the left hind paw of a suspension of Mycobacterium tubercolusis in mineral oil (500 micrograms 100 microliters-1). Controls were injected with 100 microliters mineral oil. 2. Withdrawal latencies to thermal stimuli of the inflamed paw, the contralateral and both paws of control rats were measured at daily intervals after injection by the plantar test. 3. After detection of the pain threshold, rat spinal cords were removed and horizontal dorsal slices were mounted in a 3-compartment bath to measure electrically-evoked release of substance P-like immunoreactivity (SP-LI). 4. The inflamed paw of monoarthritic rats exhibited a lower pain threshold to thermal stimuli than the contralateral paw of the same animals and both paws of control rats. Inflamed paw hyperalgesia was maximal two days after injection, and declined gradually between 7 to 21 days with no evidence of excitability of withdrawal reflexes after 28 days. 5. During the 28 days study, monoarthritic rats gained less weight than control rats. 6. Electrical stimulation of the dorsal roots attached to rat isolated spinal cord slices induced a significant increase (174 +/- 18% of basal outflow which was 30.3 fmol 8 ml-1, n = 5) in SP-LI release. 7. One-week after induction of inflammation no differences in the amount of SP-LI released from the spinal cord of incomplete Freund's adjuvant-treated rats (IFA) and Freund's adjuvant-treated rats (CFA) were detected. Two weeks after, CFA spinal cord tended to release more SP-LI than IFA cords and, 21 days after injection, the spinal cord of CFA rats released significantly more peptide than IFA rats (17.8 +/- 2.8 fmol ml-1, n = 12 and 6.9 +/- 3.2 fmol ml-1, n = 9, respectively).8. Twenty-one days after treatment, the evoked release from monoarthritic rat spinal cords was increased by 263 + 42% (n = 3) in the presence of the GABAB receptor antagonist, CGP 36742 (100 micro M)which also significantly potentiated monoarthritis-induced hyperalgesia up to 45 min after injection(100 mgkg-1, i.p.).9. These findings may provide a basis for a novel approach to chronic pain therapy but also an explanation for the lack of analgesia produced by the GABAB agonist, baclofen, in chronic as compared to acute pain.
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PMID:Spinal cord SP release and hyperalgesia in monoarthritic rats: involvement of the GABAB receptor system. 753 91

The effects of local spinal applications of the substance P antagonist, CP-96,345, on the electrically-evoked discharges of nociceptive neurons were examined in the superficial spinal dorsal horn of adult rats anesthetized with sodium pentobarbital. Extracellular single-unit recordings were made from lumbar spinal dorsal horn neurons which were excited by noxious mechanical stimulation and had early and late discharges evoked by A- and C-fiber inputs, respectively, following transcutaneous electrical stimulation. CP-96,345 was applied directly onto the surface of the spinal cord close to the recording sites. A dose of 50 nmol of CP-96,345 drastically inhibited the late discharges of 80% of neurons, without affecting early discharges significantly. This study demonstrated the specific inhibitory effect of CP-96,345 on the late discharges of a restricted population of spinal dorsal horn neurons. These results illustrate the important role of substance P in nociceptive transmission mediated by primary afferent C-fibers in normal acute pain.
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PMID:The inhibitory effect of substance P antagonist, CP-96,345, on the late discharges of nociceptive neurons in the rat superficial spinal dorsal horn. 769 99

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.
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PMID:Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. 953 17

The present study had been made to study the distribution and synaptic characteristics of primary afferent C fibers and the normal chemical architecture of some neurotransmitters in spinal dorsal horn. The changes of the neurotransmitters with acute nociceptive stimulation were measured quantitatively. We demonstrated the synaptic relationships among primary afferent C fibers, inhibitory interneurons and nociceptive dorsal horn neurons and discussed their function in nociceptive transmission and modulation. These results provide evidence that acute pain evolved co-release of substance P and glutamate from C-fiber terminals may constitute a driving force for secondary activation of ascending projection neurons or of internal GABAergic antinoceciptive system directly via their receptors in the dorsal horn of the spinal cord.
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PMID:[Chemical anatomy of the nociceptive transmission and modulation in the spinal dorsal horn]. 977 83

Although there is considerable information about the mechanisms through which injury stimuli produce acute pain, recent studies indicate that there are significant long-term consequences of persistent injury. Pain is exacerbated, in part, because of a reorganization of spinal cord circuitry in the setting of persistent injury. This review describes our studies of the contribution of the primary afferent neurotransmitter, substance P (SP), to these changes. By following internalization of the SP receptor in spinal cord dorsal horn neurons, we have identified the stimuli that evoke SP release and the neurons that respond to these stimuli. Importantly, based on the intensities of stimuli required to evoke internalization, we conclude that SP is only released under conditions in which severe pain would be produced, that the release can be evoked by intense stimulation of somatic and visceral tissue, and that multiple stimulus modalities are effective. We also found that the numbers of neurons that are influenced increases dramatically in the setting of inflammation. Using a knockout strategy, we have also raised mice with a deletion of the preprotachykinin-A (PPT-A) gene, which encodes for SP and neurokinin A (NKA), and have identified a specific behavioral phenotype in which the animals do not detect a window of "pain" intensities; this window cuts across stimulus modalities. These results provide an important behavioral correlate of the receptor internalization studies. On the other hand, the allodynia (lowered pain threshold) that occurs in the setting of injury was not altered in these animals. Among the factors that could underlie injury-induced allodynia are the second messenger systems that are activated in dorsal horn neurons. Our studies have recently implicated the gamma isoform of protein kinase C (PKCgamma) in the development of nerve injury-induced neuropathic pain. Specifically, we found that although acute pain responses of mice with a deletion of PKCgamma are not altered, partial injury to the sciatic nerve (which induces a severe thermal and mechanical allodynia in the wild type mouse) is without effect in the knockout. Furthermore, the anatomical/neurochemical reorganization that typically follows sciatic nerve section does not occur in the PKCgamma mutant mice. Because the spinal cord distribution of interneurons that express PKCgamma is concentrated almost exclusively in the inner part of lamina II, we believe that changes in the properties of these neurons are key to the development of nerve injury-induced neuropathic pain conditions. Taken together, these studies emphasize that persistent pain should be considered a disease state of the nervous system, not merely a symptom of some other disease conditions. In the setting of persistent injury, the nervous system undergoes dramatic changes that exacerbate and prolong the pain condition. Our studies underscore the importance of preventing the long-term changes that result from persistent injury.
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PMID:Spinal mechanisms of acute and persistent pain. 995 97

To address the neurochemistry of the mechanisms that underlie the development of acute and persistent pain, our laboratory has been studying mice with deletions of gene products that have been implicated in nociceptive processing. We have recently raised mice with a deletion of the preprotachykinin-A gene, which encodes the peptides substance P (SP) and neurokinin A (NKA). These studies have identified a specific behavioral phenotype in which the animals do not detect a window of "pain" intensities; this window cuts across thermal, mechanical, and chemical modalities. The lowered thermal and mechanical withdrawal thresholds that are produced by tissue or nerve injury, however, were still present in the mutant mice. Thus, the behavioral manifestations of threshold changes in nociceptive processing in the setting of injury do not appear to require SP or NKA. To identify relevant neurochemical factors downstream of the primary afferent, we are also studying the dorsal horn second messenger systems that underlie the development of tissue and nerve injury-induced persistent pain states. We have recently implicated the gamma isoform of protein kinase C (PKCgamma) in the development of nerve injury-induced neuropathic pain. Acute pain processing, by contrast, is intact in the PKCgamma-null mice. Taken together, these studies emphasize that there is a distinct neurochemistry of acute and persistent pain. Persistent pain should be considered a disease state of the nervous system, not merely a prolonged acute pain symptom of some other disease conditions.
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PMID:Distinct neurochemical features of acute and persistent pain. 1039 91


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