Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen)

Vellani, Vittorio; Giacomoni, Chiara

doi:10.1155/2017/3595903

Cited by 10 publications

(12 citation statements)

References 41 publications

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“…It has been reported that the agent may cause the indirect release of noxious substances including bradykinins, serotonin, histamine and PGs (28)(29)(30). The severity of abdominal constriction induced by AA may be dependent on the production and release of pro-inflammatory cytokines from resident peritoneal macrophages and mast cells (31,32).…”

Section: Discussionmentioning

confidence: 99%

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Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Zhuang

et al. 2017

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Abstract. Nefopam, an analgesic drug, effectively elicits antinociception in the majority of noxious and thermal models in rodents. Acetaminophen is among the most commonly used analgesic and antipyretic drugs worldwide, either on prescription or over the counter. The present study aimed to investigate the analgesic activity of nefopam combined with acetaminophen, which was expected to maximize the potency of analgesia and decrease the dose of nefopam required. Three series of experiments, namely acetic acid-induced writhing tests in mice, hot plate tests in mice and tail flick tests in rats, were used to evaluate the analgesic effect. Initially, an optimum proportion of the two drugs, 3.5 mg/kg nefopam (N) + 60 mg/kg acetaminophen (A), was determined by orthogonal array design based on writhing response number. Subsequently, combinations of N and A (1.75 N + 30 A, 3.5 N + 60 A and 7.0 N + 120 A mg/kg) were determined to elicit antinociception in the writhing test (P<0.01 vs. normal saline control) in a dose-dependent manner. In the hot plate test, hot plate latencies up to 60 min after drug treatment were observed. The combination of 7.0 N + 120 A mg/kg exerted a greater cumulative antinociceptive effect throughout the observation period, with an area under the curve value of 1,156.95±199.30 area units (AU), compared with that achieved by 7.0 N mg/kg alone (632.12±62.38 AU). Furthermore, both monotherapy and compound therapy exhibited antinociception dose-dependently in the tail-flick test. However, a combination of 5.0 N + 84 A mg/kg exerted greater analgesic effect compared with 5.0 N mg/kg alone. The data obtained demonstrate that acetaminophen may enhance the antinociceptive activity of nefopam. Thus, coadministration of nefopam with acetaminophen warrants clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

“…Unlike most NSAIDs, acetaminophen administration at therapeutic doses has little or no anti-inflammatory or anti-platelet activity (29). Additionally, it does not exhibit the typical side effect profile of NSAIDs, which includes gastrointestinal tract problems and aspirininduced asthma (37,38).…”

Section: Discussionmentioning

confidence: 99%

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Zhuang

et al. 2017

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“…Activation of membrane receptors coupled to the PLC pathway leads to PKCε translocation from the cytoplasm to the plasma membrane. To study PKCε behaviour, we employed a well‐established technique (Vellani et al, ; Vellani et al, ; Vellani et al, ; Vellani et al, ; Vellani, Franchi, et al, ; Vellani & Giacomoni, ; Vellani, Prandini, et al, ). This technique involves activation of PKCε translocation in cultured DRG neurons rapidly induced (30 s) by inflammatory mediators, such as bradykinin (BK), prokineticin 2 (PK2), thrombin, and endothelin‐1, followed by fixation with 4% paraformaldehyde and 4% sucrose in PBS (50% dilution), staining for PKCε, and quantification of the number of neurons in which translocation is observed.…”

Section: Methodsmentioning

confidence: 99%

CR4056, a powerful analgesic imidazoline‐2 receptor ligand, inhibits the inflammation‐induced PKCε phosphorylation and membrane translocation in sensory neurons

Vellani

Sabatini

Milia

et al. 2019

British J Pharmacology

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Background and Purpose CR4056 is a first‐in‐class imidazoline‐2 (I2) receptor ligand characterized by potent analgesic activity in different experimental animal models of pain. In a recent phase II clinical trial, CR4056 effectively reduced pain in patients with knee osteoarthritis. In the present study, we investigated the effects of CR4056 on PKCε translocation in vitro and on PKCε activation in vivo in dorsal root ganglia (DRG) neurons. Experimental Approach Effects of CR4056 on bradykinin‐induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant‐treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals. Key Results CR4056 inhibited PKCε translocation with very rapid and long‐lasting activity. CR4056 decreased hyperalgesia and phospho‐PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved Gi proteins. The inhibition of PKCε translocation by CR4056 was independent of the α2‐adrenoeceptor and, surprisingly, was also independent of idazoxan‐sensitive I2 binding sites. The I2 agonist 2BFI had no effect alone but potentiated the activity of low concentrations of CR4056. Conclusions and Implications Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I2 receptors should be further investigated. If so, this would be a new mode of action of a highly specific I2 receptor ligand.

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“…PKCε translocation in rat sensory neurons (Vellani et al, 2020), a cellular event shared with other analgesics (Vellani & Giacomoni, 2017).…”

Section: Discussionmentioning

confidence: 99%

Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models

Sala

Ferrari²,

Lanza³

et al. 2020

British J Pharmacology

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Prolonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I 2 receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I 2 receptor ligand CR4056 could improve efficacy and safety of morphine and explored the mechanisms of the CR4056-opioid interaction. Experimental Approach: We used the complete Freund's adjuvant (CFA) model in rats to study the effects of treatments on hyperalgesia, morphine tolerance and microglia activation as measured by immunofluorescence. Opioid-induced adverse effects were assessed in rodent models of morphine-induced constipation, sedation (open field, sedation rating scale, and rotarod), physical dependence (naloxoneinduced withdrawal), and abuse (conditioned place preference-associated reward). Chemiluminescence assays tested CR4056 as allosteric modulator of μ-opioid receptors. Key Results: CR4056 (ED 50 = 4.88 mgÁkg −1) and morphine (ED 50 = 2.07 mgÁkg −1) synergized in reducing CFA-induced hyperalgesia (ED 50 = 0.52 mgÁkg −1 ; 1:1 combination). Consistently, low doses of CR4056 (1 mgÁkg −1) spared one third of the cumulative morphine dose administered during 4 days and prevented/reversed the development of tolerance to morphine anti-hyperalgesia. These opioid-sparing effects were associated with decreased activation of microglia, independent of CR4056 interactions on μ-opioid receptors. Importantly, the low doses of CR4056 and morphine that synergize in analgesia did not induce constipation, sedation, physical dependence, or place preference.

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Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen)

Cited by 10 publications

References 41 publications

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

CR4056, a powerful analgesic imidazoline‐2 receptor ligand, inhibits the inflammation‐induced PKCε phosphorylation and membrane translocation in sensory neurons

Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models

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