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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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in vitro nociceptor neuroplasticity associated with in vivo opioid induced hyperalgesia
The Journal of Neuroscience, 2019Co-Authors: Eugen V Khomula, Dioneia Araldi, Jon D. LevineAbstract:Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, two days after systemic fentanyl, rats had also developed Hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5nM) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a mu-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4-positive and IB4-negative neurons. This sensitizing effect of fentanyl was reversed in weakly IB4-positive DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. SIGNIFICANCE STATEMENT Clinically used mu-opioid receptor agonists such as fentanyl can produce hyperalgesia and Hyperalgesic priming. We report on an in vitro model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming, induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid naive and opioid primed animals, and provide evidence for the important role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.
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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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mu opioid receptor mor biased agonists induce biphasic dose dependent hyperalgesia and analgesia and Hyperalgesic priming in the rat
Neuroscience, 2018Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Abstract Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and Hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E2 (PGE2) produced prolonged hyperalgesia (priming). OIH and priming were both prevented by intrathecal treatment with an oligodeoxynucleotide (ODN) antisense (AS) for MOR mRNA. Agents that reverse Type I (the protein translation inhibitor cordycepin) and Type II (combination of Src and mitogen-activated protein kinase [MAPK] inhibitors) priming, or their combination, did not reverse priming induced by local administration of PZM21 or TRV130. While systemic PZM21 at higher doses (1 and 10 mg/kg) induced analgesia, lower doses (0.001, 0.01, 0.1, and 0.3 mg/kg) induced hyperalgesia; all doses induced priming. Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.
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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.
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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in vitro nociceptor neuroplasticity associated with in vivo opioid induced hyperalgesia
The Journal of Neuroscience, 2019Co-Authors: Eugen V Khomula, Dioneia Araldi, Jon D. LevineAbstract:Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, two days after systemic fentanyl, rats had also developed Hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5nM) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a mu-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4-positive and IB4-negative neurons. This sensitizing effect of fentanyl was reversed in weakly IB4-positive DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. SIGNIFICANCE STATEMENT Clinically used mu-opioid receptor agonists such as fentanyl can produce hyperalgesia and Hyperalgesic priming. We report on an in vitro model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming, induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid naive and opioid primed animals, and provide evidence for the important role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.
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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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mu opioid receptor mor biased agonists induce biphasic dose dependent hyperalgesia and analgesia and Hyperalgesic priming in the rat
Neuroscience, 2018Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Abstract Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and Hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E2 (PGE2) produced prolonged hyperalgesia (priming). OIH and priming were both prevented by intrathecal treatment with an oligodeoxynucleotide (ODN) antisense (AS) for MOR mRNA. Agents that reverse Type I (the protein translation inhibitor cordycepin) and Type II (combination of Src and mitogen-activated protein kinase [MAPK] inhibitors) priming, or their combination, did not reverse priming induced by local administration of PZM21 or TRV130. While systemic PZM21 at higher doses (1 and 10 mg/kg) induced analgesia, lower doses (0.001, 0.01, 0.1, and 0.3 mg/kg) induced hyperalgesia; all doses induced priming. Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.
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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.
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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mu opioid receptor mor biased agonists induce biphasic dose dependent hyperalgesia and analgesia and Hyperalgesic priming in the rat
Neuroscience, 2018Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Abstract Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and Hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E2 (PGE2) produced prolonged hyperalgesia (priming). OIH and priming were both prevented by intrathecal treatment with an oligodeoxynucleotide (ODN) antisense (AS) for MOR mRNA. Agents that reverse Type I (the protein translation inhibitor cordycepin) and Type II (combination of Src and mitogen-activated protein kinase [MAPK] inhibitors) priming, or their combination, did not reverse priming induced by local administration of PZM21 or TRV130. While systemic PZM21 at higher doses (1 and 10 mg/kg) induced analgesia, lower doses (0.001, 0.01, 0.1, and 0.3 mg/kg) induced hyperalgesia; all doses induced priming. Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.
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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.
Nayef E Saade - One of the best experts on this subject based on the ideXlab platform.
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potent analgesic and anti inflammatory actions of a novel thymulin related peptide in the rat
British Journal of Pharmacology, 2002Co-Authors: Bared Safiehgarabedian, Mireille Dardenne, Jean Marie Pleau, Nayef E SaadeAbstract:The present study examines the effect of PAT (peptide analogue of thymulin) in two rat models of inflammatory hyperalgesia induced by either i.pl. (1.25 μg in 50 μl saline) or i.p. (50 μg in 100 μl) injections of endotoxin ET. Pretreatment with PAT (1, 5 or 25 μg in 100 μl saline, i.p.) decreased, in a dose dependent manner, both mechanical hyperalgesia, determined by the paw pressure (PP) test and thermal hyperalgesia determined by the hot plate (HP), the paw immersion (PI) and the tail flick (TF) tests. Compared to the tripeptides K(D)PT and K(D)PV, known to antagonize interleukin (IL)-1β or IL-1β and PGE2 mechanisms, PAT, at lower dosages, exerted stronger anti-Hyperalgesic effects. When compared with the effect of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drugs (NSAID), PAT demonstrated equal analgesic actions. Pretreatment with PAT, reduced significantly the increased concentration of IL-1β, IL-6, TNF-α and NGF due to i.pl. injection of ET. Injection of i.p. ET produced sickness behaviour characterized by hyperalgesia and fever. Pretreatment with PAT prevented the hyperalgesia and maintained the body temperature within the normal range and was accompanied by a down-regulation of the levels of pro-inflammatory cytokines and PGE2 in the liver. PAT, in all doses used, did not result in any evident changes in the physiological parameters or in the normal behaviour of the rats. The anti-Hyperalgesic and anti-inflammatory effects of PAT can be attributed, at least partially, to the down-regulation of pro-inflammatory mediators. Keywords: Inflammation, hyperalgesia, analgesics, septic shock, cytokines, NGF, thymulin Introduction Both chronic pain and acute pain are often the byproduct of inflammatory reactions to injuries and diseases. Most treatments aim primarily to relieve pain by reducing the inflammatory reactions. There are two major classes of anti-inflammatory drugs that have been used for the treatment of inflammation and the resulting pain: the non-steroidal anti-inflammatory drugs (NSAID) and the corticosteroids. Both of these drugs act by inhibiting the production of prostaglandins (PG), especially PGE2, which plays a key role in inflammation (Vane et al., 1994). Cyclo-oxygenase (COX) is the pivotal enzyme in prostaglandin biosynthesis and exists in two isoforms: COX-1 (constitutive and responsible for physiological functions) and COX-2 (inducible and involved mainly in inflammation). Inhibition of COX-1 has been associated with ulcerogenic side effects, whereas targeting of COX-2 is considered to result in therapeutic effects (Mitchell & Warner, 1999). Corticosteroids, which also inhibit the synthesis of PGE2, are well known for their immunosuppressive effects (Barnes & Adcock, 1993; Gold et al., 2001). Therefore, an ideal anti-inflammatory drug with analgesic effect would be a molecule that does not interfere with COX-1 and does not suppress the immune system. Recently, there has been interest in the development of peptides that might have properties of an ideal anti-inflammatory and analgesic drug (Hamilton et al., 1999; Huber et al., 2000). Thymulin is a peptide hormone derived from thymic epithelial cells, shown to bind to specific receptors on human lymphoblastoid T-cell lines (Pleau et al., 1980) and to be mainly involved in several immune functions (Safieh-Garabedian et al., 1992). Recently, several reports have indicated that, besides its immunoblotting role, thymulin is capable of interacting directly and/or indirectly with the nervous system (for review, see Safieh-Garabedian et al., 1999). For example, thymulin injections, in high concentrations, reduced the ET-induced mechanical and thermal hyperalgesia and the elevation of cytokine levels (Safieh-Garabedian et al., 1996; 1998). On the other hand, thymulin injections, in low concentrations, resulted in hyperalgesia, an effect partly mediated via PGE2 and cytokines (Safieh-Garabedian et al., 2000). It has been also shown that these actions were abolished by sub-diaphragmatic vagotomy, indicating supraspinal mechanisms and the involvement of capsaicin sensitive primary afferent fibers in mediating the Hyperalgesic actions of thymulin (Saade et al., 1998). In this study, we report on the analgesic and anti-inflammatory actions of a synthetic peptide analogue of thymulin (PAT), which was initially synthesized with the potential for clinical applications as an immunomodulating agent (Pleau et al., 1979). To characterize the analgesic and anti-inflammatory actions of PAT, we utilized two animal models of inflammation and hyperalgesia, using intraplantar (i.pl.) and intraperitoneal (i.p.) endotoxin (ET) injections. It has been previously shown that pro-inflammatory cytokines and NGF are important mediators of ET-induced hyperalgesia (Safieh-Garabedian et al., 1997). The aim of this study was to investigate whether PAT could affect the inflammatory hyperalgesia and to compare the efficacy of this molecule to that of steroidal, NSAID and peptides with known anti-inflammatory and anti-Hyperalgesic actions.
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involvement of capsaicin sensitive primary afferents in thymulin induced hyperalgesia
Journal of Neuroimmunology, 1998Co-Authors: Nayef E Saade, Salim A Kanaan, Stella Major, Samir Atweh, Suhayl J. Jabbur, Bared SafiehgarabedianAbstract:Abstract Intraplantar (5 ng) or intraperitoneal (50 ng) injections of thymulin, produced both thermal and mechanical hyperalgesia in rats. In this report, we show that ablation of capsaicin sensitive primary afferents (CSPA) can alter or abolish thymulin-induced hyperalgesia. Different groups of rats were subjected to either treatment with capsaicin or to surgical subdiaphragmatic vagotomy (SDV). Both capsaicin and SDV reduced significantly thymulin-induced hyperalgesia. On the other hand, these treatments elicited differential effects on the modulation by thymulin of the levels of nerve growth factor and interleukin 1β. We conclude that the Hyperalgesic effects of i.p. thymulin are mainly mediated through the CSPA fibers.
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Involvement of capsaicin sensitive primary afferents in thymulin-induced hyperalgesia.
Journal of neuroimmunology, 1998Co-Authors: Nayef E Saade, Salim A Kanaan, S C Major, Samir Atweh, Suhayl J. Jabbur, Bared Safieh-garabedianAbstract:Intraplantar (5 ng) or intraperitoneal (50 ng) injections of thymulin, produced both thermal and mechanical hyperalgesia in rats. In this report, we show that ablation of capsaicin sensitive primary afferents (CSPA) can alter or abolish thymulin-induced hyperalgesia. Different groups of rats were subjected to either treatment with capsaicin or to surgical subdiaphragmatic vagotomy (SDV). Both capsaicin and SDV reduced significantly thymulin-induced hyperalgesia. On the other hand, these treatments elicited differential effects on the modulation by thymulin of the levels of nerve growth factor and interleukin 1beta. We conclude that the Hyperalgesic effects of i.p. thymulin are mainly mediated through the CSPA fibers.
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Effect of transdermal opioids in experimentally induced superficial, deep and Hyperalgesic pain.
British journal of pharmacology, 2011Co-Authors: Trine Andresen, Lars Arendt-nielsen, Camilla Staahl, A Oksche, Heikki Mansikka, Asbjørn Mohr DrewesAbstract:BACKGROUND AND PURPOSE Chronic pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ-opioid receptor. Buprenorphine and its active metabolite are believed to act through µ-, κ- and δ-receptors and may therefore possess different analgesic and anti-Hyperalgesic effects compared with pure µ-receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti-Hyperalgesic effects of buprenorphine and fentanyl. EXPERIMENTAL APPROACH Twenty-two healthy volunteers were randomized to treatment with transdermal buprenorphine (20 µg·h−1, 144 h), fentanyl (25 µg·h−1, 72 h) or placebo patches in a double-blind, cross-over experimental pain study. The experimental pain tests (phasic pain, sensitization) involved pressure at the tibial bone, cutaneous electrical and thermal stimulation, intramuscular nerve growth factor, UVB light burn injury model and intradermal capsaicin-induced hyperalgesia. Pain testing was carried out at baseline, 24, 48, 72 and 144 h after application of the drugs. KEY RESULTS Compared with placebo, buprenorphine, but not fentanyl, significantly attenuated pressure at the tibial bone as well as pressure pain in the primary Hyperalgesic area induced by UVB light The two drugs were equipotent and better than placebo against cutaneous thermal pain stimulation), but failed to show significant analgesic effect to cutaneous electrical stimulation, nerve growth factor-induced muscle soreness and to capsaicin-induced hyperalgesia. CONCLUSIONS AND IMPLICATIONS Buprenorphine, but not fentanyl, showed analgesic effects against experimentally induced, bone-associated pain and primary hyperalgesia compared with placebo. These tissue- and modality-differentiated properties may reflect the variable effects of opioid drugs observed in individual patients.
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Inhibitory effect of capsaicin evoked trigeminal pain on warmth sensation and warmth evoked potentials
Experimental Brain Research, 2005Co-Authors: Massimiliano Valeriani, Michele Tinazzi, Domenica Pera, Domenico Restuccia, Liala Armas, Toni Maiese, Pietro Tonali, Lars Arendt-nielsenAbstract:The aim of the study was to evaluate the effect of tonic pain evoked by topical application of capsaicin on the somatosensory sensation of warmth. The warmth pathways were studied in ten healthy subjects by recording the scalp potentials evoked by non-painful warm laser stimuli delivered on both the right and left perioral region (warmth C-fiber related laser-evoked potentials (C-LEPs)). Tonic pain was induced by topical capsaicin application above the lateral part of the right upper lip. The area of primary and secondary hyperalgesia were mapped. C-LEPs were obtained from 31 scalp electrodes before, during, and after capsaicin application. C-LEPs from the right perioral region were evoked by laser stimuli delivered to the area of secondary hyperalgesia during capsaicin application and on both the areas of primary and secondary hyperalgesia after capsaicin removal. While the lateralized N1/P1 component (around 185 ms of latency) was not affected by the capsaicin, the amplitudes of the later vertex C-LEPs (around 260 and 410 ms of latency for the N2a and P2 potentials, respectively) evoked from the secondary Hyperalgesic area on the right side and from a symmetrical non-Hyperalgesic area on the left perioral region were significantly decreased during capsaicin application and after capsaicin removal, as compared with the baseline recordings. At the same times, the rating of the laser-evoked warmth sensation was reduced significantly. This inhibitory effect can occur at brainstem level and is possibly due to: 1) trigemino-cortico-trigeminal circuits, similar to those mediating the classical diffuse noxious inhibitory control, or 2) an increased background activity of the capsaicin-insensitive A-fibers, which mediate the secondary hyperalgesia. Probably due to a peripheral inhibitory mechanism, neither reliable C-LEP components nor warmth sensation were evoked by laser pulses delivered to the primary Hyperalgesic area. This is the first neurophysiological evidence in humans of an inhibitory effect of pain on warmth sensation.
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The effect of Ketamine on stimulation of primary and secondary Hyperalgesic areas induced by capsaicin--a double-blind, placebo-controlled, human experimental study.
Pain, 1996Co-Authors: Ole Kaeseler Andersen, Sven Felsby, Lone Nicolaisen, Peter Bjerring, Troels S. Jensen, Lars Arendt-nielsenAbstract:The non-competitive NMDA-antagonist, Ketamine, was infused (i.v.) in healthy volunteers to study the effect on central excitability with the presence of cutaneous hyperalgesia. Hyperalgesia was established experimentally on the dorsum of the foot by topical application of capsaicin (1%). Different thermal and mechanical conditioning stimuli were applied to the primary and secondary Hyperalgesic areas to modulate the central nociceptive excitability monitored by the nociceptive reflex. When the elicited reflex was combined with an activation of the secondary Hyperalgesic area by continuous, non-painful, electrical stimulation, a facilitation of the reflex was observed. This indicates that summation of activity in non-nociceptive and nociceptive afferents can occur under mild pathological conditions. Conditioning thermal stimuli of the primary Hyperalgesic area were employed to intensify the allodynia prior to testing this interaction between tactile and nociceptive activity. The same reflex facilitation was inhibited by Ketamine. Furthermore, Ketamine decreased the pain intensity associated with the stimuli eliciting the reflex. Psychophysical measures to single and repeated electrical and thermal (laser) stimuli applied within the Hyperalgesic areas were also obtained. The intensity of pain sensations produced by single, painful, electrical stimuli applied to the primary Hyperalgesic region was reduced after Ketamine infusion. Finally, five repeated, electrical stimuli applied to the secondary Hyperalgesic area were used to assess the temporal summation threshold. Ketamine caused an increase in the summation threshold compared to the placebo treatment. In conclusion, these results demonstrate that (1) summation of activity in non-nociceptive and nociceptive afferents occurs under Hyperalgesic conditions and, (2) this summation can be inhibited by NMDA-antagonists. Therefore, the study shows an apparent involvement of NMDA-receptors in some of the central mechanisms underlying secondary hyperalgesia.