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Jon D. Levine - One of the best experts on this subject based on the ideXlab platform.
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Opioid-Induced Hyperalgesic Priming in Single Nociceptors.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Eugen V Khomula, Dioneia Araldi, Ivan J Bonet, Jon D. LevineAbstract:Clinical μ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E2 (PGE2) Hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and MAP kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (
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systemic morphine produces dose dependent nociceptor mediated biphasic changes in nociceptive threshold and neuroplasticity
Neuroscience, 2019Co-Authors: Luiz F Ferrari, Oliver Bogen, Dioneia Araldi, Paul G. Green, Jon D. LevineAbstract:Abstract We investigated the dose dependence of the role of nociceptors in opioid-induced side-effects, Hyperalgesia and pain chronification, in the rat. Systemic morphine produced a dose-dependent biphasic change in mechanical nociceptive threshold. At lower doses (0.003–0.03 mg/kg, s.c.) morphine induced mechanical Hyperalgesia, while higher doses (1–10 mg/kg, s.c.) induced analgesia. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to mu-opioid receptor (MOR) mRNA, attenuated both Hyperalgesia and analgesia. 5 days after systemic morphine (0.03–10 mg/kg s.c.), mechanical Hyperalgesia produced by intradermal (i.d.) prostaglandin E2 (PGE2) was prolonged, indicating hyperalgesic priming at the peripheral terminal of the nociceptor. The Hyperalgesia induced by i.t. PGE2 (400 ng/10 µl), in groups that received 0.03 (that induced Hyperalgesia) or 3 mg/kg (that induced analgesia) morphine, was also prolonged, indicating priming at the central terminal of the nociceptor. The prolongation of the Hyperalgesia induced by i.d. or i.t. PGE2, in rats previously treated with either a hyperalgesic (0.03 mg/kg, s.c.) or analgesic (3 mg/kg, s.c.) dose, was reversed by i.d. or i.t. injection of the protein translation inhibitor cordycepin (1 µg), indicative of Type I priming at both terminals. Although pretreatment with MOR antisense had no effect on priming induced by 0.03 mg/kg morphine, it completely prevented priming by 3 mg/kg morphine, in both terminals. Thus, the induction of Hyperalgesia, but not priming, by low-dose morphine, is MOR-dependent. In contrast, induction of both Hyperalgesia and priming by high-dose morphine is MOR-dependent. The receptor at which low-dose morphine acts to produce priming remains to be established.
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Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms.
Pain, 2017Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced Hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced Hyperalgesia and prolongation of prostaglandin E2-induced Hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced Hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone-induced Hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in MOR signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and mitogen-activated protein kinase inhibitors were coadministered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund's adjuvant was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming, and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.
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gi protein coupled 5 ht1b d receptor agonist sumatriptan induces type i hyperalgesic priming
Pain, 2016Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Abstract We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical Hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Ce, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 Hyperalgesia. The prolongation of PGE2 Hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 Hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
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Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.
Pain, 2016Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical Hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Ce, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 Hyperalgesia. The prolongation of PGE2 Hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 Hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
Dioneia Araldi - One of the best experts on this subject based on the ideXlab platform.
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Opioid-Induced Hyperalgesic Priming in Single Nociceptors.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Eugen V Khomula, Dioneia Araldi, Ivan J Bonet, Jon D. LevineAbstract:Clinical μ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E2 (PGE2) Hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and MAP kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (
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systemic morphine produces dose dependent nociceptor mediated biphasic changes in nociceptive threshold and neuroplasticity
Neuroscience, 2019Co-Authors: Luiz F Ferrari, Oliver Bogen, Dioneia Araldi, Paul G. Green, Jon D. LevineAbstract:Abstract We investigated the dose dependence of the role of nociceptors in opioid-induced side-effects, Hyperalgesia and pain chronification, in the rat. Systemic morphine produced a dose-dependent biphasic change in mechanical nociceptive threshold. At lower doses (0.003–0.03 mg/kg, s.c.) morphine induced mechanical Hyperalgesia, while higher doses (1–10 mg/kg, s.c.) induced analgesia. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to mu-opioid receptor (MOR) mRNA, attenuated both Hyperalgesia and analgesia. 5 days after systemic morphine (0.03–10 mg/kg s.c.), mechanical Hyperalgesia produced by intradermal (i.d.) prostaglandin E2 (PGE2) was prolonged, indicating hyperalgesic priming at the peripheral terminal of the nociceptor. The Hyperalgesia induced by i.t. PGE2 (400 ng/10 µl), in groups that received 0.03 (that induced Hyperalgesia) or 3 mg/kg (that induced analgesia) morphine, was also prolonged, indicating priming at the central terminal of the nociceptor. The prolongation of the Hyperalgesia induced by i.d. or i.t. PGE2, in rats previously treated with either a hyperalgesic (0.03 mg/kg, s.c.) or analgesic (3 mg/kg, s.c.) dose, was reversed by i.d. or i.t. injection of the protein translation inhibitor cordycepin (1 µg), indicative of Type I priming at both terminals. Although pretreatment with MOR antisense had no effect on priming induced by 0.03 mg/kg morphine, it completely prevented priming by 3 mg/kg morphine, in both terminals. Thus, the induction of Hyperalgesia, but not priming, by low-dose morphine, is MOR-dependent. In contrast, induction of both Hyperalgesia and priming by high-dose morphine is MOR-dependent. The receptor at which low-dose morphine acts to produce priming remains to be established.
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Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms.
Pain, 2017Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced Hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced Hyperalgesia and prolongation of prostaglandin E2-induced Hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced Hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone-induced Hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in MOR signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and mitogen-activated protein kinase inhibitors were coadministered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund's adjuvant was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming, and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.
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gi protein coupled 5 ht1b d receptor agonist sumatriptan induces type i hyperalgesic priming
Pain, 2016Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Abstract We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical Hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Ce, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 Hyperalgesia. The prolongation of PGE2 Hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 Hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
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Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.
Pain, 2016Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical Hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Ce, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 Hyperalgesia. The prolongation of PGE2 Hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 Hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
Luiz F Ferrari - One of the best experts on this subject based on the ideXlab platform.
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systemic morphine produces dose dependent nociceptor mediated biphasic changes in nociceptive threshold and neuroplasticity
Neuroscience, 2019Co-Authors: Luiz F Ferrari, Oliver Bogen, Dioneia Araldi, Paul G. Green, Jon D. LevineAbstract:Abstract We investigated the dose dependence of the role of nociceptors in opioid-induced side-effects, Hyperalgesia and pain chronification, in the rat. Systemic morphine produced a dose-dependent biphasic change in mechanical nociceptive threshold. At lower doses (0.003–0.03 mg/kg, s.c.) morphine induced mechanical Hyperalgesia, while higher doses (1–10 mg/kg, s.c.) induced analgesia. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to mu-opioid receptor (MOR) mRNA, attenuated both Hyperalgesia and analgesia. 5 days after systemic morphine (0.03–10 mg/kg s.c.), mechanical Hyperalgesia produced by intradermal (i.d.) prostaglandin E2 (PGE2) was prolonged, indicating hyperalgesic priming at the peripheral terminal of the nociceptor. The Hyperalgesia induced by i.t. PGE2 (400 ng/10 µl), in groups that received 0.03 (that induced Hyperalgesia) or 3 mg/kg (that induced analgesia) morphine, was also prolonged, indicating priming at the central terminal of the nociceptor. The prolongation of the Hyperalgesia induced by i.d. or i.t. PGE2, in rats previously treated with either a hyperalgesic (0.03 mg/kg, s.c.) or analgesic (3 mg/kg, s.c.) dose, was reversed by i.d. or i.t. injection of the protein translation inhibitor cordycepin (1 µg), indicative of Type I priming at both terminals. Although pretreatment with MOR antisense had no effect on priming induced by 0.03 mg/kg morphine, it completely prevented priming by 3 mg/kg morphine, in both terminals. Thus, the induction of Hyperalgesia, but not priming, by low-dose morphine, is MOR-dependent. In contrast, induction of both Hyperalgesia and priming by high-dose morphine is MOR-dependent. The receptor at which low-dose morphine acts to produce priming remains to be established.
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Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms.
Pain, 2017Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced Hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced Hyperalgesia and prolongation of prostaglandin E2-induced Hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced Hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone-induced Hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in MOR signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and mitogen-activated protein kinase inhibitors were coadministered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund's adjuvant was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming, and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.
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gi protein coupled 5 ht1b d receptor agonist sumatriptan induces type i hyperalgesic priming
Pain, 2016Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Abstract We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical Hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Ce, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 Hyperalgesia. The prolongation of PGE2 Hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 Hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
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Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.
Pain, 2016Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical Hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Ce, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 Hyperalgesia. The prolongation of PGE2 Hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 Hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
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repeated mu opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain
The Journal of Neuroscience, 2015Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical Hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) Hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Ce (PKCe), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCe, dependence; (3) prolongation of Hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. SIGNIFICANCE STATEMENT The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.
S.h. Ferreira - One of the best experts on this subject based on the ideXlab platform.
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Participation of Prostaglandins in Inflammatory Pain
Prostaglandins–Immunopharmacology, 2013Co-Authors: S.h. FerreiraAbstract:ABSTRACT Our suggestion that the antialgic effect of aspirin-like drugs resulted from the prevention of the development of the Hyperalgesia due to the blockade of prostaglandins generation at the inflammatory site, has been supported by findings from several independent laboratories. In this communication we review three recent observations which stress the importance of prostaglandin in inflammatory pain and enlarge the understanding of the mechanism of the analgesic action of aspirin-like drugs and possibly of opioids. We shall discuss a) the “immediate” hyperalgesic effect of prostacyclin (PGI2); b) the central antialgic effect of aspirin-like drugs on carrageenin rat paw Hyperalgesia, and c) the peripheral analgesic effect of morphine, enkephalins and opioids antagonists on the “delayed” hyperalgesic effect of prostaglandins E2.
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Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone
British journal of pharmacology, 1997Co-Authors: S.h. Ferreira, Fernando Q. Cunha, Berenice B Lorenzetti, M A Michelin, Mauro Perretti, Rod J. Flower, S. PooleAbstract:The effect of dexamethasone, lipocorton-12–26 and an antiserum to lipocortin-12–26 (LCPS1) upon the hyperalgesic activities in rats of carrageenin, bradykinin, tumour necrosis factor α (TNFα), interleukin-12, interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin Eβ (PGE2) and dopamine were investigated in a model of mechanical Hyperalgesia. Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 μg), bradykinin (500 ng), TNFα (2.5 pg), IL-1β (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE2 (100 ng) and dopamine (10 μg), were inhibited by pretreatment with dexamethasone (0.5 mg kg−1, subcutaneously, s.c., or 0.04–5.0 μg/paw). Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1β (0.5 pg) by dexamethasone (0.5 mg kg−1, s.c.) was reversed by LCPS1 (0.5 ml kg−1, injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNFα (2.5 pg) and IL-1β (0.5 pg), but not responses to PGE2 (100 ng), were inhibited by pretreatment with lipocortin-12–26 (100 μg/paw). Also, lipocortin-12–26 (30 and 100 μg ml−1) and dexamethasone (10 μg ml−1) inhibited TNFα release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 μg ml−1), and LCPS1 partially reversed the inhibition by dexamethasone. These data are consistent with an important role for endogenous lipocortin-12–26 in mediating the anti-hyperalgesic effect of dexamethasone, with inhibiton of TNFα production by lipocortin-12–26 contributing, in part, to this role. Although arachidonic acid by itself was not hyperalgesic, the hyperalgesic response to IL-1β (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 μg) and the potentiated response was inhibited by dexamethasone (50 μg, i.pl.) and lipocortin-12–26 (100 μg, i.pl.). Also, lipocortin-12–26 (30 and 100 μg ml−1) inhibited/abolished PGE2 release by J774 cells stimulated with LPS (3 μg ml−1). These data suggest that, in inflammatory Hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A2, by dexamethasone and lipocortin-12–26 accounts for the anti-hyperalgesic effects of these agents. The above data support the notion that induction of lipocortin by dexamethasone plays a major role in the inhibition by dexamethasone of inflammatory Hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNFα, IL-1β and IL-6, and provides additional evidence that the biological activity of lipocortin resides within the peptide lipocortin-12–26. Further, the data suggest that inhibition of lipocortin-12–26 of eicosanoid production by COX-2 also contributes to the anti-hyperalgesic effect of lipocortin-1.
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Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception.
Neuropharmacology, 1994Co-Authors: S.h. Ferreira, B B LorenzettiAbstract:In the present investigation we have tested the hypothesis that spinal glutamate release by inflammatory stimuli causes Hyperalgesia through sensitization of the primary sensory neurons associated with nociception. In these experiments, the rat paw Hyperalgesia pressure test in which inflammatory Hyperalgesia is blocked by the intraplantar administration of morphine (MPH) or SNAP, a NO donor was used. Glutamate and glutamatergic ionotropic agonists such as NMDA or AMPA injected intrathecally (i.t.) caused a dose-dependent Hyperalgesia. Quisqualate or ACPD, both of which are glutamate metabotropic receptor agonists, had no hyperalgesic effect. The hyperalgesic response to glutamate and NMDA injected i.t. was antagonized by the intraplantar (i.pl.) injection of either MPH or SNAP. This observation indicates that the Hyperalgesia induced by glutamate acting through an NMDA pre-synaptic receptor causes sensitization of the primary sensory neurons. Confirming that the analgesia by i.pl. injection of SNAP or MPH was due to an action in primary peripheral sensory neurons, it was shown that pretreatment of the paws with methylene blue (MB, an inhibitor of guanylate cyclase) or with MB and l-NMMA (an inhibitor of NO synthase) abolished their respective analgesic effect. AMPA i.t. induced Hyperalgesia was not inhibited by either i.pl. administration of MPH or SNAP, indicating that its hyperalgesic capacity results from an action at a site other than the primary sensory neuron. Administration of the NMDA antagonists AP5 and MK801, but not the AMPA antagonist CNQX, inhibited the Hyperalgesia induced by intraplantar injections of PGE2 or carrageenin. Overall, our results indicate that Hyperalgesia evoked by an inflammatory stimulus in this model causes a continuous release of spinal glutamate which, via an NMDA-type receptor, promotes a retrograde sensitization of the primary sensory neurons.
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Bradykinin release of TNF-α plays a key role in the development of inflammatory Hyperalgesia
Agents and Actions, 1993Co-Authors: S.h. Ferreira, Berenice B Lorenzetti, F. Q. Cunha, S. PooleAbstract:Using specific antisera for IL-1β and IL-8, as well as cyclooxygenase inhibitors and propranolol, we have demonstrated that these cytokines are responsible for the prostaglandin and sympathetic components of carrageenin-induced Hyperalgesia in the rat paw test. The release of IL-1β and IL-8 is preceded by the liberation of TNF-α. We have also tested in a nociceptive model the effects of bradykinin and a specific bradykinin antagonist, HOE 140, on the Hyperalgesia induced by carrageenin and lipopolysaccharide (LPS). Bradykinin-induced Hyperalgesia was abolished by HOE 140 and by treatment of the paws with anti-TNF-α antisera. HOE 140 significantly inhibited the Hyperalgesia induced by carrageenin and LPS. It is suggested that in these two models bradykinin is associated with the release of hyperalgesic cytokines.
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the pivotal role of tumour necrosis factor α in the development of inflammatory Hyperalgesia
British Journal of Pharmacology, 1992Co-Authors: Fernando Q. Cunha, B B Lorenzetti, Stephen Poole, S.h. FerreiraAbstract:Abstract 1. The hyperalgesic activities in rats of interleukin-1 beta (IL-1 beta), IL-6, IL-8, tumour necrosis factor alpha (TNF alpha) and carrageenin were investigated. 2. IL-6 activated the previously delineated IL-1/prostaglandin hyperalgesic pathway but not the IL-8/sympathetic mediated hyperalgesic pathway. 3. TNF alpha and carrageenin activated both pathways. 4. Antiserum neutralizing endogenous TNF alpha abolished the response to carrageenin whereas antisera neutralizing endogenous IL-1 beta, IL-6 and IL-8 each partially inhibited the response. 5. The combination of antisera neutralizing endogenous IL-1 beta + IL-8 or IL-6 + IL-8 abolished the response to carrageenin. 6. These results show that TNF alpha has an early and crucial role in the development of inflammatory Hyperalgesia. 7. The delineation of the role of TNF alpha, IL-1 beta, IL-6 and IL-8 in the development of inflammatory Hyperalgesia taken together with the finding that the production of these cytokines is inhibited by steroidal anti-inflammatory drugs provides a mechanism of action for these drugs in the treatment of inflammatory Hyperalgesia.
Ana Tereza Gomes Guerrero - One of the best experts on this subject based on the ideXlab platform.
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the role of paf pafr signaling in zymosan induced articular inflammatory Hyperalgesia
Naunyn-schmiedebergs Archives of Pharmacology, 2013Co-Authors: Fernando Q. Cunha, Sérgio H. Ferreira, Ana Tereza Gomes Guerrero, Ana C Zaperlon, Silvio M Vieira, Larissa G Pinto, Waldiceu A Verri, Thiago M CunhaAbstract:Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular Hyperalgesia in a model of joint inflammation. Zymosan-induced articular Hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR−/−). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 μg/joint), time- and PAFR-dependent articular Hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular Hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced Hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB4 as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory Hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory Hyperalgesia.
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The role of PAF/PAFR signaling in zymosan-induced articular inflammatory Hyperalgesia
Naunyn-Schmiedeberg's Archives of Pharmacology, 2013Co-Authors: Ana Tereza Gomes Guerrero, Fernando Q. Cunha, Sérgio H. Ferreira, Ana C Zaperlon, Silvio M Vieira, Larissa G Pinto, Waldiceu A Verri, Thiago M CunhaAbstract:Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular Hyperalgesia in a model of joint inflammation. Zymosan-induced articular Hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR^−/−). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 μg/joint), time- and PAFR-dependent articular Hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular Hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced Hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB_4 as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory Hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory Hyperalgesia.
