The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
David J Clark - One of the best experts on this subject based on the ideXlab platform.
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loss of μ opioid receptor signaling in nociceptors but not microglia abrogates morphine tolerance without disrupting analgesia
Nature Medicine, 2017Co-Authors: Gregory Corder, David J Clark, Vivianne L Tawfik, D Wang, Elizabeth I Sypek, Jasmine R Dickinson, Chaudy Sotoudeh, Ben A Barres, Christopher J Bohlen, Gregory ScherrerAbstract:μ opioid receptors (MORs) expressed on primary afferent nociceptor neurons are responsible for two maladaptive side-effects of chronic opioid use: opioid tolerance and Opioid-Induced Hyperalgesia (pain). A combination therapy of opioid receptor agonism plus peripheral-restricted MOR antagonism abrogates these side-effects while preserving opioid analgesia in rodent models of peri-operative and chronic pain.
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the multiple pdz domain protein mpdz mupp1 regulates opioid tolerance and opioid induced Hyperalgesia
BMC Genomics, 2016Co-Authors: Robin Donaldson, Peyman Sahbaie, Deyong Liang, Ming Zheng, David L Dill, Gary Peltz, Kari J Buck, David J ClarkAbstract:Opioids are a mainstay for the treatment of chronic pain. Unfortunately, therapy-limiting maladaptations such as loss of treatment effect (tolerance), and paradoxical Opioid-Induced Hyperalgesia (OIH) can occur. The objective of this study was to identify genes responsible for opioid tolerance and OIH. These studies used a well-established model of ascending morphine administration to induce tolerance, OIH and other opioid maladaptations in 23 strains of inbred mice. Genome-wide computational genetic mapping was then applied to the data in combination with a false discovery rate filter. Transgenic mice, gene expression experiments and immunoprecipitation assays were used to confirm the functional roles of the most strongly linked gene. The behavioral data processed using computational genetic mapping and false discovery rate filtering provided several strongly linked biologically plausible gene associations. The strongest of these was the highly polymorphic Mpdz gene coding for the post-synaptic scaffolding protein Mpdz/MUPP1. Heterozygous Mpdz +/− mice displayed reduced opioid tolerance and OIH. Mpdz gene expression and Mpdz/MUPP1 protein levels were lower in the spinal cords of low-adapting 129S1/Svlm mice than in high-adapting C57BL/6 mice. Morphine did not alter Mpdz expression levels. In addition, association of Mpdz/MUPP1 with its known binding partner CaMKII did not differ between these high- and low-adapting strains. The degrees of maladaptive changes in response to repeated administration of morphine vary greatly across inbred strains of mice. Variants of the multiple PDZ domain gene Mpdz may contribute to the observed inter-strain variability in tolerance and OIH by virtue of changes in the level of their expression.
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epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure
Molecular Pain, 2016Co-Authors: Peyman Sahbaie, Deyong Liang, Xiaoyou Shi, Yuan Sun, David J ClarkAbstract:BackgroundOpioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause Opioid-Induced Hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved.ResultsFour days of ascending doses of morphine treatment caused Opioid-Induced Hyperalgesia and reduced opioid analgesic efficacy in mice. Both Opioid-Induced Hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitatio...
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preprotachykinin a gene disruption attenuates nociceptive sensitivity after opioid administration and incision by peripheral and spinal mechanisms in mice
The Journal of Pain, 2012Co-Authors: Peyman Sahbaie, Deyong Liang, Xiaoyou Shi, David C Yeomans, Tianzhi Guo, Yanli Qiao, Wade S Kingery, David J ClarkAbstract:Abstract The preprotachykinin A gene (ppt-A) codes for Substance P (SP), supports nociceptive sensitization, and modulates inflammatory responses after incision. Repeated opioid use produces paradoxical pain sensitization—termed Opioid-Induced Hyperalgesia (OIH) —which can exacerbate pain after incision. Here the contribution of SP to peri-incisional nociceptive sensitization and nociceptive mediator production after opioid treatment was examined utilizing ppt-A knockout (−/−) mice and the neurokinin (NK1) receptor antagonist LY303870. Less mechanical allodynia was observed in ppt - A −/− mice compared to wild types (wt) after morphine treatment both before and after incision. Moreover, LY303870 administered with morphine reduced incisional Hyperalgesia in wt mice. Incision after saline or escalating morphine treatment upregulated skin IL-1β, IL-6, G-CSF and MIP-1α levels in ppt-A −/− and wt mice similarly. However, chronic morphine treatment greatly exacerbated increases in skin nerve growth factor levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent upregulation of prodynorphin, NMDA1 and NK1 receptor expression in spinal cord was seen after morphine treatment and incision. A similar pattern was seen for 5-HT3 receptor expression in tissue from dorsal root ganglia. Therefore, SP may work at both central and peripheral sites to enhance nociceptive sensitization after morphine treatment and incision. Perspective These studies show that SP signaling modulates enhanced nerve growth factor production and changes in neuronal gene expression seen after incision in mice previously exposed to morphine.
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analgesic tolerance without demonstrable opioid induced Hyperalgesia a double blinded randomized placebo controlled trial of sustained release morphine for treatment of chronic nonradicular low back pain
Pain, 2012Co-Authors: Nicole Darcy, Martin S Angst, Caitlin Brady, Abigail K Zamora, Chelsea A Young, Anna Clemenson, David J ClarkAbstract:Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently Opioid-Induced Hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop Opioid-Induced Hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not Opioid-Induced Hyperalgesia. Improvements in pain and functional ability were observed.
Martin S Angst - One of the best experts on this subject based on the ideXlab platform.
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intraoperative use of remifentanil for tiva postoperative pain acute tolerance and opioid induced Hyperalgesia
Journal of Cardiothoracic and Vascular Anesthesia, 2015Co-Authors: Martin S AngstAbstract:REMIFENTANIL IS frequently the opioid of choice when relying on total intravenous anesthetic (TIVA) protocols. The unique pharmacokinetic properties of remifentanil afford a fast onset of action and a predictable and rapid recovery independent of the infusion duration. The high lipid solubility and low ionization of remifentanil at physiological pH allow for its quick transfer from blood to central nervous system binding sites as mirrored by its fast onset of action. The very short elimination half-life and stable context-sensitive half time reflect the exceptionally high clearance of remifentanil by plasma and tissue esterases. In the context of TIVA, these pharmacokinetic properties are ideal to meet anesthetics needs with the rapid up-and-down titration of remifentanil and the exposure to relatively high cumulative doses, as such use hardy affects recovery time. While the advantageous pharmacokinetic properties of remifentanil favor its liberal use, significant concern exist among clinicians that such use may negatively affect postoperative pain. More specifically, severe postoperative pain after the intraoperative use of remifentanil has repeatedly been linked to the development of acute tolerance and/or opioidinduced Hyperalgesia (OIH). The claim has also been made that remifentanil, compared to other opioids, is particularly prone to induce acute tolerance and OIH due to its high potency and specific pharmacokinetic properties. The purpose of this topical review is to examine whether or not the intraoperative use of remifentanil has a unique negative impact on postoperative pain by inducing acute tolerance and/or OIH. The review will highlight 3 distinct phenomena associated with the intraoperative use of remifentanil: (1) the impact of an abrupt analgesic offset on spontaneous pain, (2) the development of acute tolerance and/or OIH as indicated by an aggravation of spontaneous pain, and (3) the development of OIH as indicated by an aggravation of wound Hyperalgesia. Distinguishing between spontaneous pain and wound Hyperalgesia is important as these phenomena are mechanistically distinct and lack a strong correlation. However, it is not uncommon that
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analgesic tolerance without demonstrable opioid induced Hyperalgesia a double blinded randomized placebo controlled trial of sustained release morphine for treatment of chronic nonradicular low back pain
Pain, 2012Co-Authors: Nicole Darcy, Martin S Angst, Caitlin Brady, Abigail K Zamora, Chelsea A Young, Anna Clemenson, David J ClarkAbstract:Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently Opioid-Induced Hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop Opioid-Induced Hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not Opioid-Induced Hyperalgesia. Improvements in pain and functional ability were observed.
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opioid pharmacotherapy for chronic non cancer pain in the united states a research guideline for developing an evidence base
The Journal of Pain, 2010Co-Authors: Richard C Chapman, Martin S Angst, David L Lipschitz, Roger Chou, Richard C Denisco, Gary W Donaldson, Perry G Fine, Kathleen M Foley, Rollin M Gallagher, Aaron M GilsonAbstract:Abstract This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, Opioid-Induced Hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence. Perspective Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP.
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opioid induced Hyperalgesia in humans molecular mechanisms and clinical considerations
The Clinical Journal of Pain, 2008Co-Authors: Martin S Angst, David A ClarkAbstract:Abstract Opioid-Induced Hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.
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opioid induced Hyperalgesia a qualitative systematic review
Anesthesiology, 2006Co-Authors: Martin S Angst, David J ClarkAbstract:Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as Opioid-Induced Hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning Opioid-Induced Hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.
Jon D. Levine - One of the best experts on this subject based on the ideXlab platform.
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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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role of nociceptor toll like receptor 4 tlr4 in opioid induced Hyperalgesia and hyperalgesic priming
The Journal of Neuroscience, 2019Co-Authors: Dioneia Araldi, Oliver Bogen, Paul G. Green, Jon D. LevineAbstract:In addition to analgesia, opioids produce Opioid-Induced Hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced Hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that Hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E2 Hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C e (PKCe) AS-ODN also prevented LDM-induced Hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4+ and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced Hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCe, HDM-induced analgesia, and priming are neither TLR4 nor PKCe dependent. OIH produced by LDM is mediated by both IB4+ and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4+ and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed.SIGNIFICANCE STATEMENT Opioid-Induced Hyperalgesia (OIH) and priming are common side effects of opioid agonists such as morphine, which acts at μ-opioid receptors. We demonstrate that OIH and priming induced by systemic low-dose morphine (LDM) share action at Toll-like receptor 4 (TLR4) and signaling via protein kinase C e (PKCe) in common, whereas systemic high-dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCe dependent. OIH produced by systemic LDM is mediated by isolectin B4-positive (IB4+) and peptidergic nociceptors, whereas priming is dependent on a different class of nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4+ and peptidergic nociceptors. Our findings may provide useful information for the use of low-dose opioids combined with nonopioid analgesics to treat pain and opioid use disorders.
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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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role of gpcr mu opioid receptor tyrosine kinase epidermal growth factor crosstalk in opioid induced hyperalgesic priming type ii
Pain, 2018Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: Opioid-Induced Hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced Hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors. Because the epidermal growth factor receptor (EGFR) participates in MOR signaling, we tested its role in type II priming. The EGFR inhibitor, tyrphostin AG 1478, prevented the induction of prolonged PGE2-induced Hyperalgesia, but not OIH, when tested out to 30 days after DAMGO. However, even when repeatedly injected, an EGFR agonist did not induce Hyperalgesia or priming. A phosphopeptide, which blocks the interaction of Src, focal adhesion kinase (FAK), and EGFR, also prevented DAMGO-induced prolongation of PGE2 Hyperalgesia, but only partially attenuated the induction of OIH. Inhibitors of Src and mitogen-activated protein kinase (MAPK) also only attenuated OIH. Inhibitors of matrix metalloproteinase, which cleaves EGF from membrane protein, markedly attenuated the expression, but did not prevent the induction, of prolongation of PGE2 Hyperalgesia. Thus, although the induction of prolongation of PGE2-induced Hyperalgesia at the peripheral terminal of peptidergic nociceptor is dependent on Src, FAK, EGFR, and MAPK signaling, Src, FAK, and MAPK signaling is only partially involved in the induction of OIH.
Maria Foy - One of the best experts on this subject based on the ideXlab platform.
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ketamine infusion for sickle cell pain crisis refractory to opioids a case report and review of literature
Annals of Hematology, 2014Co-Authors: Dipesh Uprety, Aurangzeb Baber, Maria FoyAbstract:This article reports a rare case of the use of low-dose ketamine infusion as an adjuvant to opioids to treat pain in sickle cell disease. A 31-year-old African-American male with history of sickle cell disease presented to the emergency department with complaints of chest tightness, multiple joint pain, and headache for 1 week. His vital signs and physical examination were unremarkable. His admission lab included hemoglobin of 8.4 g/dl, reticulocyte count of 16.3 %, bilirubin of 1.7 mg/dl, and LDH of 1,267 U/l. Chest X-ray showed middle and lower lobe opacity and interstitial thickening. He was treated for acute pain crisis and community-acquired pneumonia with intravenous fluids, supplemental oxygen, and intravenous levofloxacin. He was placed on fentanyl patient-controlled analgesia (PCA), oxycodone, ketorolac, and methadone with co-analgesic gabapentin and venlafaxine. Over the course of his hospitalization, his chest pain resolved, but the joint pains continued. He was then transferred to the ICU and was discharged a day later after 7 days of ketamine infusion. Ketamine is a noncompetitive antagonist at the N-methyl-d-aspartate (NMDA) receptor. This property has been shown to modulate opioid tolerance and Opioid-Induced Hyperalgesia. There have been a very few published reports on the use of low-dose ketamine in sickle cell pain management. A PubMed search revealed four published articles (Table 1). Fourteen out of the 17 cases (82.35 %) who received ketamine infusion showed improvement in self-reported pain intensity and significant reduction in opioid dosage. Only one patient (5.9 %) developed serious side effect leading to discontinuation of the drug. A low-dose ketamine can be an option for pain control in sickle cell disease. Randomized trial is required to establish this benefit of ketamine over currently available therapies.
Dioneia Araldi - One of the best experts on this subject based on the ideXlab platform.
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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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role of nociceptor toll like receptor 4 tlr4 in opioid induced Hyperalgesia and hyperalgesic priming
The Journal of Neuroscience, 2019Co-Authors: Dioneia Araldi, Oliver Bogen, Paul G. Green, Jon D. LevineAbstract:In addition to analgesia, opioids produce Opioid-Induced Hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced Hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that Hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E2 Hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C e (PKCe) AS-ODN also prevented LDM-induced Hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4+ and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced Hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCe, HDM-induced analgesia, and priming are neither TLR4 nor PKCe dependent. OIH produced by LDM is mediated by both IB4+ and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4+ and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed.SIGNIFICANCE STATEMENT Opioid-Induced Hyperalgesia (OIH) and priming are common side effects of opioid agonists such as morphine, which acts at μ-opioid receptors. We demonstrate that OIH and priming induced by systemic low-dose morphine (LDM) share action at Toll-like receptor 4 (TLR4) and signaling via protein kinase C e (PKCe) in common, whereas systemic high-dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCe dependent. OIH produced by systemic LDM is mediated by isolectin B4-positive (IB4+) and peptidergic nociceptors, whereas priming is dependent on a different class of nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4+ and peptidergic nociceptors. Our findings may provide useful information for the use of low-dose opioids combined with nonopioid analgesics to treat pain and opioid use disorders.
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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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role of gpcr mu opioid receptor tyrosine kinase epidermal growth factor crosstalk in opioid induced hyperalgesic priming type ii
Pain, 2018Co-Authors: Dioneia Araldi, Luiz F Ferrari, Jon D. LevineAbstract:Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: Opioid-Induced Hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced Hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors. Because the epidermal growth factor receptor (EGFR) participates in MOR signaling, we tested its role in type II priming. The EGFR inhibitor, tyrphostin AG 1478, prevented the induction of prolonged PGE2-induced Hyperalgesia, but not OIH, when tested out to 30 days after DAMGO. However, even when repeatedly injected, an EGFR agonist did not induce Hyperalgesia or priming. A phosphopeptide, which blocks the interaction of Src, focal adhesion kinase (FAK), and EGFR, also prevented DAMGO-induced prolongation of PGE2 Hyperalgesia, but only partially attenuated the induction of OIH. Inhibitors of Src and mitogen-activated protein kinase (MAPK) also only attenuated OIH. Inhibitors of matrix metalloproteinase, which cleaves EGF from membrane protein, markedly attenuated the expression, but did not prevent the induction, of prolongation of PGE2 Hyperalgesia. Thus, although the induction of prolongation of PGE2-induced Hyperalgesia at the peripheral terminal of peptidergic nociceptor is dependent on Src, FAK, EGFR, and MAPK signaling, Src, FAK, and MAPK signaling is only partially involved in the induction of OIH.