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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The roles of N-methyl-D-aspartate (NMDA) receptors and protein kinase C (PKC) are critical in generating and maintaining a variety of sustained neuronal responses. In the nociceptive (pain-sensing) system, tissue injury or repetitive stimulation of small-diameter afferent fibres triggers a dramatic increase in discharge (wind-up) or prolonged depolarization of spinal cord neurons. This central sensitization can neither be induced nor maintained when NMDA receptor channels are blocked. In the trigeminal subnucleus caudalis (a centre for processing nociceptive information from the orofacial areas), a mu-opioid receptor agonist causes a sustained increase in NMDA-activated currents by activating intracellular PKC. There is also evidence that PKC enhances NMDA-receptor-mediated glutamate responses and regulates long-term potentiation of synaptic transmission. Despite the importance of NMDA-receptors and PKC, the mechanism by which PKC alters the NMDA response has remained unclear. Here we examine the actions of intracellularly applied PKC on NMDA-activated currents in isolated trigeminal neurons. We find that PKC potentiates the NMDA response by increasing the probability of channel openings and by reducing the voltage-dependent Mg2+ block of NMDA-receptor channels.
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PMID:Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. 137 27

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.
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PMID:Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury. 139 64

Bradykinin is one of several pro-inflammatory, pain-inducing substances produced during inflammation--the body's response to injury. In previous work we have shown that bradykinin and guanosine-5'-O-3-thiotriphosphate increase excitability in a subpopulation of cultured neonatal rat dorsal root ganglion neurons. We now describe experiments in which the mechanism underlying the stimulatory action of these two substances has been examined in more detail. Using the whole-cell voltage-clamp technique, bradykinin-sensitive cells were distinguished by their response to a 1-s depolarizing voltage-pulse which evoked more than one inward current during the step command. The secondary inward currents are likely to represent action potentials generated at the poorly clamped neurites of these cells. Bradykinin- and guanosine-5'-O-3-thiotriphosphate-induced changes in excitability were measured indirectly by a change in the number of inward currents recorded during the 1-s depolarizing voltage-step. The effect of activators and inhibitors of protein kinase C, arachidonic acid metabolism, G-protein activation and release of intracellular Ca2+ were examined on this response. In the presence of extracellular staurosporine (1.0 microM) or nordihydroguaiaretic acid (10 microM), these excitatory effects were reduced but not abolished, whilst indomethacin (20 microM) had no effect. Intracellular application of guanosine-5'-O-2-thiodiphosphate (10 mM) or ryanodine (100 microM) substantially reduced the effect of bradykinin. The excitatory effect of internal guanosine-5'-O-3-thiotriphosphate (500 microM) occurred gradually over time, and this was mimicked by internal application of myo-inositol 1,4,5-trisphosphorothioate (1.0 microM). From the results, it is proposed that G-protein activation is an essential component of the bradykinin response, which may also require a Ca(2+)-activated conductance modulated by protein kinase C and lipoxygenase metabolites of arachidonic acid.
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PMID:G-protein mediation in nociceptive signal transduction: an investigation into the excitatory action of bradykinin in a subpopulation of cultured rat sensory neurons. 140 41

The whole-cell patch-clamp technique was used to record Ba2+ currents through voltage-activated calcium channels in the clonal dorsal root ganglion cell line F11-B9. The pain-producing peptide bradykinin (BK; 100 nM) reduced the sustained Ba2+ current in F11-B9 cells by 30%. In cultures prelabeled with 3H-arachidonic acid and tested under ionic conditions similar to those used for recording Ba2+ currents, BK also induced a concentration-dependent, transient, 2.7-fold accumulation of 3H-diacylglycerol. Both the elevation of 3H-diacylglycerol and the inhibition of Ba2+ current began within 5 sec following BK exposure, and the effective concentration range of BK was similar for the 2 responses. In whole-cell recordings, extracellularly applied 1-oleoyl-2-acetylglycerol (OAG; 0.5-5 microM) mimicked the degree of block and occluded the block of sustained current by BK. Another protein kinase C (PKC) activator, 1,2-dioctanoylglycerol (diC8), blocked 70-100% of sustained current when applied intracellularly or extracellularly at 5 microM, whereas extracellular application of ethylene glycol dioctanoate (5 microM), an analog reported not to stimulate PKC, inhibited only 14% of sustained current. The pseudosubstrate peptide PKC19-36 (2 microM in pipette) and the lipid staurosporine (100 nM in pipette), both inhibitors of PKC, reduced the effects of maximal concentrations of OAG or BK by 55-60%. Dynorphin A applied intracellularly (2 microM) as a control for nonspecific effects of PKC19-36 did not inhibit the block of sustained current by BK. These data are consistent with the hypothesis that BK inhibits whole-cell sustained Ba2+ current in F11-B9 cells via a mechanism that involves activation of PKC.
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PMID:Inhibition by bradykinin of voltage-activated barium current in a rat dorsal root ganglion cell line: role of protein kinase C. 201 Aug 9

Recent evidence suggests that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, have in common certain neural substrates such as activation of the N-methyl-D-aspartate (NMDA) receptor and the subsequent intracellular activation of protein kinase C and nitric oxide. Should common cellular elements be involved in hyperalgesia and morphine tolerance, these cellular and intracellular commonalities might be expected to result in interactions between these two phenomena. Indeed, our previous studies have shown that thermal hyperalgesia develops when animals are made tolerant to the antinociceptive effects of morphine. In this study, we examined the hypothesis that reduction of morphine antinociception occurs following unilateral ligation of the rats's sciatic nerve, a procedure which produces symptoms of a neuropathic pain syndrome including thermal hyperalgesia. When tested using the paw-withdrawal test on day 8 (D8) after either nerve ligation or sham operation, a single intrathecal treatment with 10 micrograms morphine sulfate (30 min after administration) produced significant antinociception in sham-operated rats but not in nerve-injured ones. These results also were obtained when thermal hyperalgesia was reversed in nerve-injured rats by the non-competitive NMDA receptor antagonist MK-801. Consistently, 8 days after sciatic nerve ligation but not after a sham operation, an approximately 6-fold rightward shift occurred in the morphine antinociceptive dose-response curve. This rightward shift of the morphine antinociceptive dose-response curve did not occur at 24 h after either nerve ligation or sham operation. In addition, once daily treatment with 10 nmol MK-801 from D2 to D7 after nerve ligation prevented both the development of thermal hyperalgesia and the rightward shift of the morphine antinociceptive dose-response curve on D8. The results indicate that the antinociceptive effects of morphine are reduced in nerve-injured rats in the absence of daily exposure to morphine and that the NMDA receptor activation may have a critical role in mechanisms of this phenomenon. These data provide further evidence indicating that interactions do occur between neural mechanisms underlying thermal hyperalgesia and morphine tolerance.
Pain 1995 Jun
PMID:Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain. 889 58

The development of tolerance to the analgesic effects of morphine as well as morphine dependence were greatly reduced by co-administration with morphine of GM1 ganglioside, a substance reported to block the translocation of protein kinase C (PKC) from cytosol to membrane of neurons. Rats made tolerant to intrathecal administration of morphine showed increased membrane-bound PKC in the superficial layers (laminae I and II) of the spinal cord dorsal horn but not in deeper layers. This increase was prevented by co-administration with morphine of GM1 ganglioside. These results indicate that the translocation and activation of PKC may be a critical step in the development of opiate tolerance and dependence. Modulation of PKC translocation and activation may prove useful for the management of pain and opiate addiction.
Pain 1995 Jun
PMID:The development of morphine tolerance and dependence is associated with translocation of protein kinase C. 889 58

We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persistent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal stimulation. Furthermore, we have assessed changes in membrane-associated PKC in spinal cord in response to both noxious chemical and thermal stimulation. Nociceptive responses, to a hindpaw injection of 50 microliters of 2.5% formalin, and flexion reflex thresholds, to mechanical stimulation (Randall-Selitto test) in the hindpaw contralateral to a thermal injury (15 sec immersion in water at 55 degrees C), were assessed following intrathecal injection of PKC inhibitors (GF 109203X or chelerythrine). 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 spinal cord sections, were assessed in rats after noxious chemical (50 microliters of 5.0% formalin) and noxious thermal (90 sec immersion in water at 55 degrees C) stimulation. Inhibitors of PKC (GF 109203X, chelerythrine), produced significant reductions of nociceptive responses to 2.5% formalin, as well as a significant reduction in the mechanical hyperalgesia in the hindpaw contralateral to a thermal injury. In addition, both noxious chemical and thermal stimulation produced significant increases in specific 3H-PDBu binding in the dorsal horn of the lumbar spinal cord, likely reflecting alterations in membrane-associated PKC. The results provide both pharmacological and anatomical evidence that persistent pain produced by chemical stimulation with formalin and mechanical hyperalgesia in the hindpaw contralateral to a thermal injury are influenced by the translocation and activation of PKC in spinal cord dorsal horn neurons.
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PMID:Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12,13-dibutyrate binding in spinal cord dorsal horn as well as persistent pain and hyperalgesia, which is reduced by inhibition of protein kinase C. 775 9

Increased pain sensitivity (hyperalgesia) and persistent nociception following peripheral tissue injury depends both on an increase in the sensitivity of primary afferent nociceptors at the site of injury (peripheral sensitization), and on an increase in the excitability of neurons in the central nervous system (central sensitization). We will review evidence that central sensitization, and the persistent nociception it leads to, are dependent on an action of glutamate and aspartate at excitatory amino acid (EAA) receptors. Additional evidence will be presented implicating a role of various intracellular second messengers that are coupled to EAA receptors (nitric oxide, arachidonic acid, and protein kinase C) to central sensitization and persistent nociception following tissue injury. Finally, we will examine the evidence for a contribution of molecular events, including noxious stimulus-induced expression of immediate-early genes such as c-fos to persistent nociception.
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PMID:The role of excitatory amino acid receptors and intracellular messengers in persistent nociception after tissue injury in rats. 791 27

1. Sensitization of dorsal horn neurons is thought to play an important role in pain perception, secondary hyperalgesia, and allodynia. Recent experimental evidence suggests that the sensitization of dorsal horn neurons is induced by combined increased release of excitatory amino acids and peptides in the spinal cord dorsal horn from nociceptive primary afferents due to an injury-caused barrage of impulses. We tested the hypothesis that protein kinase C (PKC) is involved as a second messenger in this process of neuronal sensitization. To activate PKC, infusion of a phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] into the dorsal horn through a microdialysis fiber was used. During TPA infusion the background activity of spinothalamic (STT) neurons increased substantially. After TPA application, while the background activity of the STT neurons was still increased, the responses evoked by either innocuous or noxious mechanical stimulation of the cutaneous receptive field did not change from the control level. However, 1 h after TPA administration the background activity returned to the control level and responses to innocuous mechanical stimuli were significantly elevated. The responses of STT cells to noxious heat and noxious mechanical stimuli did not change significantly after TPA administration. When a phorbol ester that does not activate PKC was applied (alpha-TPA), no significant changes in background or evoked activity of STT cells were observed. Our results provide evidence that PKC may play an important role in the process of sensitization of dorsal horn neurons to innocuous mechanical stimuli.
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PMID:The effect of phorbol esters on the responses of primate spinothalamic neurons to mechanical and thermal stimuli. 817 22

The effects of beta-phorbol 12,13-dibutyrate (PDBu) on the discharge properties of slowly conducting knee joint afferents (group III and group IV fibers) were studied to determine the role of protein kinase C in nociception. Extracellular single unit recordings were made from small filaments dissected from the medial articular nerve in cats anesthetized with alpha-chloralose. PDBu was applied intra-arterially close to the joint in concentrations of 10(-6) up to 10(-4) M. The afferents were classified as low-threshold and high-threshold units with regard to their sensitivity to passive noxious and innocuous movements of the knee joint. Following PDBu application, an excitation occurred in 28% of the group III and in 40% of the group IV fibers. An enhancement of responses to passive movements of the joint (sensitization) occurred in 37% of group III and 19% of group IV afferents. In summary, 37.5% of the low-threshold and 50% of the high-threshold fibers proved to be sensitive to PDBu. Most of the PDBu-positive units responded also to bradykinin, whereas only a few PDBu-positive units were sensitive to prostaglandin I2 and E2. We conclude from these results that, in a distinct population of slowly conducting joint afferents, protein kinase C is likely to be involved in the process of transduction. Thus, pain and hyperalgesia may be mediated at least partly by intracellular mechanisms that are linked to protein kinase C.
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PMID:The effects of phorbol ester on slowly conducting afferents of the cat's knee joint. 838 19


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