Sara González-Rodríguez

Freie Universität Berlin, Berlín, Berlin, Germany

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Publications (7)14.11 Total impact

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    ABSTRACT: The hypernociceptive role played by the chemokine CCL2, and its main receptor, CCR2, in pathological settings is being increasingly recognized. We aimed to characterize the involvement of spinal CCL2 in the hyperalgesia due to the intratibial inoculation of fibrosarcoma NCTC 2472 cells in mice. The intrathecal (i.t.) administration of the CCR2 antagonist RS 504393 (1-3 μg) or an anti-CCL2 antibody inhibited tumoral hyperalgesia. No change in the expression of spinal CCR2 was detected by western blot, whereas immunohistochemical experiments demonstrated increased CCL2 staining at the superficial laminae of the spinal cord ipsilateral to the tumor. This spinal CCL2 does not seem to be released from nociceptors since CCL2 mRNA and CCL2 levels in DRGs, as measured by RT-PCR and ELISA, remain unmodified in tumor-bearing mice. In contrast, immunohistochemical assays demonstrated the spinal up-regulations of GFAP and Iba-1, respective markers of astroglia and microglia, and the expression of CCL2 in both types of glial cells at the superficial laminae of the spinal cord of tumor-bearing mice. Finally, since CCL2 could induce astroglial or microglial activation, we studied whether the blockade of CCR2 could inhibit the increased spinal glial expression. GFAP, but not Iba-1, up-regulation was reduced in tumor-bearing mice treated for 3 days with i.t. RS 504393, indicating that spinal CCL2 acts as an astroglial activator in this setting. The participation at spinal level of CCL2/CCR2 in tumoral hypernociception, together with its previously described involvement at periphery, makes attractive the modulation of this system for the alleviation of neoplastic pain.
    Cellular and Molecular Neurobiology 10/2013; 34(1). DOI:10.1007/s10571-013-9995-7 · 2.51 Impact Factor
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    Melanie Busch-Dienstfertig · Sara González-Rodríguez ·
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    ABSTRACT: During inflammation, several mediators directly or indirectly induce pain including pro-inflammatory cytokines and there is evidence that the JAK-STAT pathway is involved in the formation of pronociceptive cytokines. The same pathway, however, is also of importance for anti-inflammatory cytokines such as IL-4 to counteract the inflammatory reaction and-as it seems based on the current literature-nociceptive symptoms. Current therapeutic approaches targeting molecules of the JAK-STAT signaling cascade are auspicious but as this review demonstrates, more experimental and clinical studies are required to decipher the specific contribution of this pathway in the modulation of pain.
    10/2013; 2(4):e27638. DOI:10.4161/jkst.27638
  • Marta Pevida · Sara González-Rodríguez · Ana Lastra · Agustín Hidalgo · Luis Menéndez · Ana Baamonde ·
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    ABSTRACT: The participation of the chemokine CCL2 (monocyte chemoattractant protein-1) in inflammatory and neuropathic pain is well established. Furthermore, the release of CCL2 from a NCTC 2472 cells-evoked tumor and its involvement in the upregulation of calcium channel α2δ1 subunit of nociceptors was demonstrated. In the present experiments, we have tried to determine whether the increase in CCL2 levels is a common property of painful tumors and, in consequence, the administration of a chemokine receptor type 2 (CCR2) antagonist can inhibit tumoral hypernociception. CCL2 levels were measured by ELISA in the tumoral region of mice intratibially inoculated with NCTC 2472 or B16-F10 cells, and the antihyperalgesic and antiallodynic effects evoked by the administration of the selective CCR2 antagonist RS 504393 were assessed. Cultured NCTC 2472 cells release CCL2 and their intratibial inoculation evokes the development of a tumor in which CCL2 levels are increased. Moreover, the systemic or peritumoral administration of RS 504393 inhibited thermal and mechanical hyperalgesia, but not mechanical allodynia evoked after the inoculation of these cells. Thermal hyperalgesia was also inhibited by the peritumoral administration of a neutralizing CCL2 antibody. In contrast, no change in CCL2 levels was observed in mice inoculated with B16-F10 cells, and RS 504393 did not inhibit the hypernociceptive reactions evoked by their intratibial inoculation. The peripheral release of CCL2 is involved in the development of thermal and mechanical hyperalgesia, but not mechanical allodynia evoked by the inoculation of NCTC 2472 cells, whereas this chemokine seems unrelated to the hypernociception induced by B16-F10 cells.
    Archiv für Experimentelle Pathologie und Pharmakologie 09/2012; 385(11):1053-61. DOI:10.1007/s00210-012-0787-2 · 2.47 Impact Factor
  • Sara González-Rodríguez · Sara Llames · Agustín Hidalgo · Ana Baamonde · Luis Menéndez ·
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    ABSTRACT: Agonists of μ-opioid receptors are currently used in the management of cancer pain. However, several data suggest that the analgesic effect of morphine can diminish during the development of experimental tumors. By using a thermal test, we have studied whether the analgesic effect evoked by morphine is altered in mice bearing two painful bone tumors. The analgesic effect evoked by systemic morphine remained unaltered after the intratibial inoculation of B16-F10 melanoma cells and was potentiated after the inoculation of NCTC 2472 osteosarcoma cells. Although the number of spinal μ-opioid receptors measured by western blot studies was not augmented in osteosarcoma-bearing mice, the analgesia evoked by intrathecal (i.t.) morphine was also enhanced. The analgesic response produced by the spinal administration of the Gi/o protein activator mastoparan was amplified, whereas the analgesic response evoked by the i.t. administration of the N-type calcium channel blocker ω-conotoxin remained unaltered. The efficacy of the GIRK channel blocker tertiapin-Q to antagonize the analgesic effect produced by a maximal dose of morphine was also increased in osteosarcoma-bearing mice. Our results seem to indicate that the analgesic effect of morphine on thermal nociception can be enhanced in response to the development of particular bone tumors in mice, being this potentiation probably related to a greater efficacy of the transduction system driven by Gi/o proteins and GIRK channels.
    Fundamental and Clinical Pharmacology 02/2011; 26(3):363-72. DOI:10.1111/j.1472-8206.2010.00921.x · 2.12 Impact Factor
  • Sara González-Rodríguez · Agustín Hidalgo · Ana Baamonde · Luis Menéndez ·
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    ABSTRACT: The analgesic efficacy of opiates can be enhanced in inflammatory states due to peripheral and spinal alterations. We describe here that the analgesic effect induced by intrathecal (i.t.) morphine assessed by measuring thermal withdrawal latencies is enhanced in carrageenan-inflamed mice. The spinal micro-opioid receptor (MOR) population is not up-regulated as demonstrated by Western blot assays. In contrast, behavioural experiments show the involvement of changes in transduction mechanisms activated by spinal opioid receptors. The i.t. administration of the nitric oxide (NO) synthase inhibitor L-NMMA (3-30 microg) antagonised with a similar potency and efficacy morphine-induced analgesia in inflamed and non-inflamed mice, discarding that an increase in NO release could be responsible of the enhancement of morphine-induced analgesia. The analgesic effects evoked by the i.t. administration of the direct G(i/o) protein activator mastoparan (0.03-10 microg), but not those induced by the N-type calcium channel blocker omega-conotoxin GVIA (3-30 ng), were potentiated in inflamed mice, suggesting that postsynaptic and not presynaptic mechanisms could be involved. Furthermore, the inhibitory effects on morphine-induced analgesia produced by the G(i/o) protein inhibitor pertussis toxin (0.1-17 ng) or the G-coupled inwardly rectifying potassium (GIRK) channels inhibitor tertiapin-Q (0.75-750 ng) were greatly enhanced in inflamed mice. These results suggest that differences in the transduction mechanism activated by MOR at postsynaptic level, probably related with GIRK channels activity, could participate in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice.
    Archiv für Experimentelle Pathologie und Pharmakologie 11/2009; 381(1):59-71. DOI:10.1007/s00210-009-0471-3 · 2.47 Impact Factor
  • Sara González-Rodríguez · Agustín Hidalgo · Ana Baamonde · Luis Menéndez ·
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    ABSTRACT: The analgesic effect induced by opiates is often potentiated during experimental inflammatory processes. We describe here that lower doses of systemic morphine are necessary to increase thermal withdrawal latencies measured in both hind paws of mice acutely inflamed with carrageenan than in healthy ones. This bilateral potentiation seems mediated through spinal opioid receptors since it is inhibited by the intrathecal (i.t.), but not intraplantar ( administration of the opioid receptor antagonist naloxone-methiodide, and also appears when morphine is i.t. administered. Furthermore, the administration of the nitric oxide (NO) synthase inhibitor, L-NMMA, or the K (ATP) (+) -channel blocker, glibenclamide, to carrageenan-inflamed mice inhibits the enhanced effect of systemic morphine in the paw that receives the injection of the drug, without affecting the potentiation observed in the contralateral one. The administration of L-NMMA also partially antagonised the analgesic effect induced by i.t. morphine in inflamed mice. Finally, the increased analgesic effect evoked by the administration of the NO donor SIN-1 either in the inflamed or in the contralateral paw of carrageenan-inflamed mice suggests that enhanced responsiveness to the peripheral analgesic effect of NO may be also underlying the bilateral potentiation of morphine-induced analgesia in acutely inflamed mice.
    Cellular and Molecular Neurobiology 09/2009; 30(1):113-21. DOI:10.1007/s10571-009-9436-9 · 2.51 Impact Factor
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    ABSTRACT: Although previous studies describe the up-regulation of purinergic P2X(3) receptors expressed at peripheral nociceptive fibers in experimental painful neoplastic processes, the analgesic efficacy of P2X(3) receptor antagonists has not been tested in these settings. We study here the effect of the P2X(3) receptor antagonist, A-317491, on thermal hyperalgesia produced by the intratibial inoculation of NCTC 2472 fibrosarcoma cells to C3H/HeJ mice. The peritumoral administration of A-317491 (10-100 microg) dose-dependently attenuated osteosarcoma-induced thermal hyperalgesia without modifying thermal latencies measured in the contralateral paws. This antihyperalgesic effect was inhibited by the coadministration of naloxone-methiodide (0.1-1 microg) or the systemic injection of the selective mu-opioid receptor antagonist cyprodime (1 mg/kg), demonstrating the involvement of peripheral mu-opioid receptors. Furthermore, the antihyperalgesic effect induced by A-317491, was antagonised by the coadministration of an anti-enkephalin antibody supporting the participation of endogenous enkephalins. Consistent with this result, the antihyperalgesic effect induced by A-317491 was dramatically enhanced by the administration of an enkephalin-degrading inhibitor, Debio 0827, as demonstrated by isobolographic analysis. This synergism opens the theoretical possibility that the combination of both types of drugs could be useful to counteract some nociceptive symptoms derived from tumor development.
    Neuroscience Letters 09/2009; 465(3):285-9. DOI:10.1016/j.neulet.2009.09.015 · 2.03 Impact Factor