Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opioid peptides and exogenous opioids such as morphine are known to exert important cardiovascular effects. However, until recently, it was not appreciated that activation of specific receptors results in a potent cardioprotective effect to reduce infarct size in experimental animals and to reduce cell death in isolated cardiomyocytes. In intact rat and rabbit hearts, nonselective opioid receptor antagonists such as naloxone and a selective delta1-opioid receptor antagonist, 7-benzylidenenaltrexone, have been shown to inhibit the cardioprotective effect of ischemic preconditioning, a phenomenon in which brief periods of ischemia protect the heart against a more prolonged period of ischemia. Selective delta(1) specific agonists such as 2-methyl-4a-alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a-alpha-octahydroquinolino[2,3,3-g]isoquinoline have been shown to exert potent cardioprotective effects in intact animals and cardiac myocytes via activation of Gi/o proteins, protein kinase C, and ultimately, the mitochondrial KATP channel. These protective effects occur immediately following drug administration, and reappear 24-48 hr post treatment. Although further studies are needed to more clearly define the mechanisms by which opioids exert their cardioprotective effects, the data accumulated and summarized in this review suggest that this class of drugs may not only be useful in alleviating the pain associated with a myocardial infarction, but may also be simultaneously reducing the size of the ultimate infarct. Since many of these drugs are already clinically available, a long period of drug development may not be necessary before the use of these drugs reaches the patient with signs of myocardial ischemia.
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PMID:Opioids and cardioprotection. 1131 16

The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been proposed that ATP, released from different cell types, initiates the sensation of pain by acting predominantly on nociceptive ionotropic purinoceptors located on sensory nerve terminals. In this study, we examined the effects of extracellular ATP on VR1. In cells expressing VR1, ATP increased the currents evoked by capsaicin or protons through activation of metabotropic P2Y(1) receptors in a protein kinase C-dependent pathway. The involvement of G(q/11)-coupled metabotropic receptors in the potentiation of VR1 response was confirmed in cells expressing both VR1 and M1 muscarinic acetylcholine receptors. In the presence of ATP, the temperature threshold for VR1 activation was reduced from 42 degrees C to 35 degrees C, such that normally nonpainful thermal stimuli (i.e., normal body temperature) were capable of activating VR1. This represents a novel mechanism through which the large amounts of ATP released from damaged cells in response to tissue trauma might trigger the sensation of pain.
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PMID:Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. 1137 11

Gabapentin (Neurontin) (GBP) is a widely prescribed analgesic used in treating pain patients with peripheral nerve injuries, diabetic neuropathy and cancer. To understand the mechanism of its action, we used the whole-cell patch recording technique to study the effects of GBP on N-methyl-D-aspartate (NMDA)-evoked currents in single dorsal horn neurons isolated from normal rats and from rats with inflammation induced by the injection of complete Freund adjuvant (CFA) to the hindpaw. We found that GBP enhanced NMDA currents in normal neurons only when protein kinase C (PKC) was added to these cells. The enhancement resulted from an increase in the affinity of glycine for NMDA receptors by GBP. In contrast, in neurons isolated from CFA-treated rats, GBP enhanced NMDA responses without any PKC treatment. Since endogenous PKC in inflamed tissue is elevated, these results suggest that GBP exerts its effects only on those cells affected by inflammatory injuries. Thus, the effects of GBP on NMDA receptors are plastic; they depend on the phosphorylation states of cells or receptors. These observations point to a new strategy for drug design. A chemical whose action depends on the state of cells would maximize its effectiveness while keeping its side-effects to a minimum.
Pain 2001 Jul
PMID:Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent. 1140 42

In previous studies we provided evidence that the gamma isoform of protein kinase C (PKCgamma) is an important contributor to the increased pain sensitivity that occurs after injury. Here we combined electrophysiological and behavioral approaches in wild-type and PKCgamma-null mice to compare the hyperexcitability of wide dynamic range neurons in lamina V of the spinal cord dorsal horn with the behavioral hyperexcitability produced by the same injury [application of a C-fiber irritant, mustard oil (MO), to the hindpaw]. Wild-type and null mice did not differ in their response to mechanical or thermal stimuli before tissue injury, and the magnitude of the response to the MO stimuli was comparable. In wild-type mice, MO produced a dramatic and progressive enhancement of the response of lamina V neurons to innocuous mechanical and thermal stimuli. The time course of the neuronal hyperexcitability paralleled the time course of the MO-induced behavioral allodynia (nocifensive behavior in response to a previously innocuous mechanical stimulus). Neuronal hyperexcitability was also manifest in the PKCgamma-null mice, but it lasted <30 min. By contrast, the behavioral allodynia produced by MO in the PKCgamma-null mice, although reduced to approximately half that of the wild-type mice, persisted long after the lamina V hyperexcitability had subsided. Because the MO-induced behavioral allodynia was completely blocked by an NMDA receptor antagonist, we conclude that PKCgamma mediates the transition from short- to long-term hyperexcitability of lamina V nociresponsive neurons but that the persistence of injury-induced pain must involve activity within multiple NMDA-dependent spinal cord circuits.
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PMID:PKCgamma contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. 1143 8

We have evaluated the contribution of differences in second messenger signalling to sex differences in inflammatory pain and its control by sex hormones. In normal male but not female rats, epinephrine-induced mechanical hyperalgesia was antagonized by inhibitors of protein kinase Cepsilon (PKCepsilon), protein kinase A (PKA) and nitric oxide synthetase (NOS). Similarly, in PKCepsilon knockout mice, a contribution of PKCepsilon to epinephrine-dependent mechanical hyperalgesia occurred in males only. In contrast, hyperalgesia induced by prostaglandin E2, in both females and males, was dependent on PKA and NO. In both sexes, inhibitors of mitogen-activated protein kinase/extracellular-signal related kinase kinase (MEK) inhibited epinephrine hyperalgesia. In gonadectomized females, the second messenger contributions to epinephrine hyperalgesia demonstrated the pattern seen in males. Administration of oestrogen to gonadectomized females fully reconstituted the phenotype of the normal female. These data demonstrate gender differences in PKCepsilon, PKA and NO signalling in epinephrine-induced hyperalgesia which are oestrogen dependent and appear to be exerted at the level of the beta-adrenergic receptor or the G-protein to which it is coupled.
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PMID:Sex hormones regulate the contribution of PKCepsilon and PKA signalling in inflammatory pain in the rat. 1145 25

Inflammatory pain, characterized by a decrease in mechanical nociceptive threshold (hyperalgesia), arises through actions of inflammatory mediators, many of which sensitize primary afferent nociceptors via G-protein-coupled receptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKCepsilon), have been implicated in primary afferent nociceptor sensitization. Here we describe a third, independent pathway that involves activation of extracellular signal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces hyperalgesia by direct action at beta(2)-adrenergic receptors on primary afferent nociceptors, stimulated phosphorylation of ERK1/2 in cultured rat dorsal root ganglion cells. This was inhibited by a beta(2)-adrenergic receptor blocker and by an inhibitor of mitogen and extracellular signal-regulated kinase kinase (MEK), which phosphorylates and activates ERK1/2. Inhibitors of G(i/o)-proteins, Ras farnesyltransferases, and MEK decreased epinephrine-induced hyper-algesia. In a similar manner, phosphorylation of ERK1/2 was also decreased by these inhibitors. Local injection of dominant active MEK produced hyperalgesia that was unaffected by PKA or PKCepsilon inhibitors. Conversely, hyperalgesia produced by agents that activate PKA or PKCepsilon was unaffected by MEK inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade acts independent of PKA or PKCepsilon as a novel signaling pathway for the production of inflammatory pain. This pathway may present a target for a new class of analgesic agents.
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PMID:Nociceptor sensitization by extracellular signal-regulated kinases. 1151 80

We examined protein kinase C gamma-like immunoreactivity (PKCgamma-LI) of trigeminothalamic neurons in the rat medullary dorsal horn (MDH) after injecting a retrograde tracer, Fluoro-Gold (FG), into the thalamus. Over 90% of FG-labeled neurons in the marginal layer (lamina I) and a few FG-labeled neurons in the superficial part of the magnocellular layer (lamina III) showed PKCgamma-LI. No PKCgamma-neurons in the substantia gelatinosa (lamina II) were labeled with FG. PKCgamma-mediated regulation of trigeminothalamic neurons may contribute to the changes in MDH activity during persistent pain.
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PMID:Protein kinase C gamma-like immunoreactivity of trigeminothalamic neurons in the medullary dorsal horn of the rat. 1154 80

Coincident with nociception, both noxious chemical stimulation of the hind paw and chronic constriction injury (CCI) of the sciatic nerve produce an increase in protein kinase C (PKC) translocation in the spinal cord of rats. Noxious stimulus-induced PKC translocation likely depends on glutamate activity at either N-methyl-D-aspartate (NMDA) receptors or group I metabotropic glutamate receptors (mGluR1/5) in the spinal cord dorsal horn. This study compares nociceptive responses to, and the alterations in membrane-associated PKC, induced by noxious chemical stimulation of the hindpaw and CCI of the sciatic nerve, as well as their modulation by both NMDA and mGluR1/5 receptor antagonists. Three groups of rats were given a single intrathecal (i.t.) injection of either vehicle, dizocilpine maleate (MK-801, 60 nmol), an NMDA receptor antagonist, or (S)-4-carboxyphenylglycine (S)-4CPG, (150 nmol), an mGluR1/5 antagonist, 10 min prior to a 50 microl of 2.5% formalin injection into the ventral surface of one hind paw. Another three groups of rats were given twice daily injections of either vehicle, MK-801 (30 nmol) or (S)-4CPG (90 nmol) i.t. for 5 days starting 30 min before CCI or sham injury of the sciatic nerve. Nociceptive responses were assessed for a 60 min period after the formalin injection in the first three groups, and tests of mechanical and cold allodynia were performed on days 4, 8, 12 and 16 after CCI for the latter three groups. Furthermore, changes in the levels of membrane-associated PKC, as assayed by quantitative autoradiography of the specific binding of [3H]-phorbol 12,13-dibutyrate ([3H]-PDBu) in the dorsal horn of the lumbar spinal cord sections, were assessed in formalin-injected rats (at 5, 25 and 60 min) and in neuropathic rats 5 days after CCI, treated (as above) with vehicle, MK-801 or (S)-4CPG. The results indicate that i.t. treatment with MK-801 significantly reduced nociceptive scores in the formalin test and also produced a significant suppression of formalin-induced increases in [3H]-PDBu binding in laminae I-II, III-VI and X of the lumbar spinal cord. In contrast, i.t. treatment with (S)-4CPG failed to significantly affect either nociceptive behaviours in the formalin test or formalin-induced increases in [3H]-PDBu binding in laminae I-II and III-VI of the lumbar spinal cord. On the other hand, i.t. treatment with either MK-801 or (S)-4CPG produced a significant reduction in mechanical and cold hypersensitivity, as well as [3H]-PDBu binding in laminae I-II and III-VI of the lumbar spinal cord, after CCI. These results suggest that while NMDA, but not mGluR1/5, receptors are involved in translocation of PKC and nociception in a model of persistent acute pain, both types of receptors influence the translocation of PKC in dorsal horn and mechanical and cold allodynia in a model of chronic neuropathic pain.
Pain 2001 Oct
PMID:Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats. 1157 41

Opioids have been thought to induce analgesia by activating the descending pain control system, especially at the level of periaqueductal gray, and regulate the neurotransmitter release through the inhibition of calcium channel. In the present study, the modulatory effects of protein kinase C and protein kinase A on the mu-opioid agonist-induced inhibition of the high-voltage activated calcium current were examined in the acutely dissociated rat periaqueductal gray neurons with the nystatin-perforated patch-clamp technique. Among 505 neurons tested, the barium current passing through the high-voltage activated calcium channels of 172 neurons (34%) were inhibited by 32+/-3% with the application of an mu-opioid agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO, 1 microM). The barium currents itself and the DAMGO-induced inhibitory effects were not affected by the application of either an adenylate cyclase activator (forskolin, 1 microM) or a protein kinase inhibitor (staurosporin, 10 nM) for 2 min. The DAMGO inhibition was completely and irreversibly antagonized by the application of a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA, 1 microM) for 2 min without any alteration of the barium current itself. However, the antagonizing effect of PMA was completely abolished by the application of 10 nM staurosporin for 2 min. After then, PMA did not show the antagonizing effect any more. Inversely, when staurosporin was applied before PMA, the antagonizing effect of PMA was also not shown. These results demonstrate that the mu-opioid agonist-induced inhibition of the periaqueductal gray neuronal high-voltage activated calcium current can be antagonized by protein kinase C activation. This finding may provide us a significant clue to understand the action mechanism of opioid-induced analgesia in the periaqueductal gray.
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PMID:Antagonizing effect of protein kinase C activation on the mu-opioid agonist-induced inhibition of high voltage-activated calcium current in rat periaqueductal gray neuron. 1159 91

This review deals with physiological and biological mechanisms of neuropathic pain, that is, pain induced by injury or disease of the nervous system. Animal models of neuropathic pain mostly use injury to a peripheral nerve, therefore, our focus is on results from nerve injury models. To make sure that the nerve injury models are related to pain, the behavior was assessed of animals following nerve injury, i.e. partial/total nerve transection/ligation or chronic nerve constriction. The following behaviors observed in such animals are considered to indicate pain: (a) autotomy, i.e. self-attack, assessed by counting the number of wounds implied, (b) hyperalgesia, i.e. strong withdrawal responses to a moderate heat stimulus, (c) allodynia, i.e. withdrawal in response to non-noxious tactile or cold stimuli. These behavioral parameters have been exploited to study the pharmacology and modulation of neuropathic pain. Nerve fibers develop abnormal ectopic excitability at or near the site of nerve injury. The mechanisms include unusual distributions of Na(+) channels, as well as abnormal responses to endogenous pain producing substances and cytokines such as tumor necrosis factor alpha (TNF-alpha). Persistent abnormal excitability of sensory nerve endings in a neuroma is considered a mechanism of stump pain after amputation. Any local nerve injury tends to spread to distant parts of the peripheral and central nervous system. This includes erratic mechano-sensitivity along the injured nerve including the cell bodies in the dorsal root ganglion (DRG) as well as ongoing activity in the dorsal horn. The spread of pathophysiology includes upregulation of nitric oxide synthase (NOS) in axotomized neurons, deafferentation hypersensitivity of spinal neurons following afferent cell death, long-term potentiation (LTP) of spinal synaptic transmission and attenuation of central pain inhibitory mechanisms. In particular, the efficacy of opioids at the spinal level is much decreased following nerve injury. Repeated or prolonged noxious stimulation and the persistent abnormal input following nerve injury activate a number of intracellular second messenger systems, implying phosphorylation by protein kinases, particularly protein kinase C (PKC). Intracellular signal cascades result in immediate early gene (IEG) induction which is considered as the overture of a widespread change in protein synthesis, a general basis for nervous system plasticity. Although these processes of increasing nervous system excitability may be considered as a strategy to compensate functional deficits following nerve injury, its by-product is widespread nervous system sensitization resulting in pain and hyperalgesia. An important sequela of nerve injury and other nervous system diseases such as virus attack is apoptosis of neurons in the peripheral and central nervous system. Apoptosis seems to induce neuronal sensitization and loss of inhibitory systems, and these irreversible processes might be in common to nervous system damage by brain trauma or ischemia as well as neuropathic pain. The cellular pathobiology including apoptosis suggests future strategies against neuropathic pain that emphasize preventive aspects.
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PMID:Pathobiology of neuropathic pain. 1169 24


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