Mechanisms of imidazoline I<sub>2</sub> receptor agonist‐induced antinociception in rats: involvement of monoaminergic neurotransmission

Siemian, Justin N.; Wang, Kaixuan; Zhang, Yanan; Li, Jun-Xu

doi:10.1111/bph.14161

Cited by 15 publications

(15 citation statements)

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“…Several I 2 receptor agonists such as 2-BFI and BU224 and the novel I 2 receptor agonist CR4056 have been shown to inhibit human recombinant MAO A activity in a concentration-dependent manner, and in vivo these drugs caused marked increases in norepinephrine and serotonin content in the rat cerebral cortex and lumbar spinal cord (Ferrari et al, 2011;see also Jones et al, 2007). Li's group has examined the involvement of the monoaminergic system in 2-BFI-and CR4056-induced antinociception in two chronic pain rat models: CFA-induced inflammatory pain and CCI-induced neuropathic pain (Siemian et al, 2018). 2-BFI induced dose-dependent antiallodynia in CCI rats; pretreatment with the selective serotonin reuptake inhibitor fluoxetine or the norepinephrine reuptake inhibitor desipramine dosedependently and significantly enhanced the effects of 2-BFI and shifted the 2-BFI dose-effect curve leftward (Siemian et al, 2018).…”

Section: Pharmacological and Neurobiological Mechanismsmentioning

confidence: 99%

“…Li's group has examined the involvement of the monoaminergic system in 2-BFI-and CR4056-induced antinociception in two chronic pain rat models: CFA-induced inflammatory pain and CCI-induced neuropathic pain (Siemian et al, 2018). 2-BFI induced dose-dependent antiallodynia in CCI rats; pretreatment with the selective serotonin reuptake inhibitor fluoxetine or the norepinephrine reuptake inhibitor desipramine dosedependently and significantly enhanced the effects of 2-BFI and shifted the 2-BFI dose-effect curve leftward (Siemian et al, 2018). The dopamine reuptake inhibitor GBR12909 failed to alter the antiallodynic effect of 2-BFI under the same condition.…”

Section: Pharmacological and Neurobiological Mechanismsmentioning

confidence: 99%

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Imidazoline Receptor System: The Past, the Present, and the Future

et al. 2019

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Section: Pharmacological and Neurobiological Mechanismsmentioning

confidence: 99%

Section: Pharmacological and Neurobiological Mechanismsmentioning

confidence: 99%

Imidazoline Receptor System: The Past, the Present, and the Future

et al. 2019

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“…Peripheral venous blood was taken from any easily accessible peripheral vein at three time-points post ROSC: 1 h, 2 days and 7 days. Plasma was obtained [13,14] and frozen at − 80°C for further experiment [15].…”

Section: Data Collection and Blood Samplingmentioning

confidence: 99%

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

Zhuang

Chen

Zhou

et al. 2020

BMC Cardiovasc Disord

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Background: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines , IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period. Methods: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays. Results: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC.Conclusion: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients.Trial registration: Clinicaltrial.gov NCT02297776, 2014-11-21.

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“…Remarkably, I2 receptors play a role in the same events that link obesity with impaired sensory behavior. Animal studies have shown that putative I2 receptor agonists inhibit neuroinflammation by decreasing spinal microglia activation, and can restore monoaminergic transmission in the descending pain systems 10,34,35 .…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial

Rovati¹,

Brambilla²,

Blicharski

et al. 2020

Osteoarthritis and Cartilage

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Objective: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. Design: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0e100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. Results: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P ¼ 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ! 27.5 kg/m 2 , N ¼ 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12e18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. Conclusions: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. Clinical trial registration number: EudraCT 2015-001136-37.

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Mechanisms of imidazoline I₂ receptor agonist‐induced antinociception in rats: involvement of monoaminergic neurotransmission

Cited by 15 publications

References 53 publications

Imidazoline Receptor System: The Past, the Present, and the Future

Imidazoline Receptor System: The Past, the Present, and the Future

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial

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Mechanisms of imidazoline I2 receptor agonist‐induced antinociception in rats: involvement of monoaminergic neurotransmission

Cited by 15 publications

References 53 publications

Imidazoline Receptor System: The Past, the Present, and the Future

Imidazoline Receptor System: The Past, the Present, and the Future

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial

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Mechanisms of imidazoline I₂ receptor agonist‐induced antinociception in rats: involvement of monoaminergic neurotransmission