An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

Journal of Pain Research, Journal Year: 2023, Volume and Issue: Volume 16, P. 1081 - 1094

Published: March 1, 2023

Abstract: Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly vulnerable populations. Despite its wide use, debate exists regarding analgesic mechanism of action (MoA) paracetamol. A growing body evidence challenged notion that paracetamol exerts effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident analgesia has multiple pathways mediated by formation bioactive AM404 metabolite central nervous system (CNS). a potent activator TRPV 1 , major contributor to neuronal response brain dorsal horn. In periaqueductal grey, activated channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides comprehensive literature review centrally located, COX-independent, MoA relates how current experimental can be translated into clinical practice. discussed this established as central, antinociceptive medication distinct from non-steroidal anti-inflammatory drugs (NSAIDs) tolerable safety profile. With establishment paracetamol, we believe preferred healthy adults, children, patients with health concerns. However, concerns remain high dose due NAPQI-mediated liver necrosis. Centrally acting paracetamol/ p -aminophenol derivatives could potentiate without increasing risk hepatoxicity. Moreover, specific allows combination other analgesics, including NSAIDs, different MoA. Future experiments better explain actions pave way discovering new analgesics benefit-to-risk ratio. Keywords: acetaminophen, AM404, analgesia, molecular targets

Language: Английский

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Differential regulation of Ca_v3.2 and Ca_v2.2 calcium channels by CB₁ receptors and cannabidiol

British Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 180(12), P. 1616 - 1633

Published: Jan. 17, 2023

Background and Purpose Cannabinoids are a promising therapeutic avenue for chronic pain. However, clinical trials often fail to report analgesic efficacy of cannabinoids. Inhibition voltage gate calcium (Ca v ) channels is one mechanism through which cannabinoids may produce analgesia. We hypothesized that cannabinoid receptor agonists target different types Ca distinct mechanisms. Experimental Approach Electrophysiological recordings from tsA‐201 cells expressing either 3.2 or 2.2 were used assess inhibition by HU‐210 cannabidiol (CBD) in the absence presence CB 1 receptor. Homology modelling assessed potential interaction sites CBD both 3.2. Analgesic effects mouse models inflammatory neuropathic Key Results (1 μM) inhibited function but had no effect on regardless co‐expression By contrast, (3 produced instead independently receptors. supported these findings, indicating binds occludes pore 3.2, not 2.2. Intrathecal alleviated thermal mechanical hypersensitivity male female mice, this was absent null mice. Conclusion Implications Our findings reveal differential modulation receptors CBD. This advances our understanding how analgesia action at voltage‐gated could influence development novel cannabinoid‐based therapeutics treatment

Language: Английский

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α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Feb. 21, 2024

Abstract Background It is now realized that Parkinson’s disease (PD) pathology extends beyond the substantia nigra, affecting both central and peripheral nervous systems, exhibits a variety of non-motor symptoms often preceding motor features. Neuroinflammation induced by activated microglia astrocytes thought to underlie these manifestations. α-Synuclein aggregation has been linked with sustained neuroinflammation in PD, aggravating neuronal degeneration; however, there still lack critical information about structural identity α-synuclein conformers activate and/or molecular pathways involved. Methods To investigate role development maintenance neuroinflammation, we used primary quiescent astrocytes, post-mortem brain tissues from PD patients A53T transgenic mice recapitulate key features PD-related inflammatory responses absence cell death, i.e., increased levels pro-inflammatory cytokines complement proteins. Biochemical -omics techniques including RNAseq secretomic analyses, combined 3D reconstruction individual live calcium imaging, were uncover mechanisms underlying glial presence oligomers vivo vitro. Results We found SDS-resistant hyper-phosphorylated oligomers, but not monomers, was correlated responses, such as elevated endogenous antibodies microglial activation. Similar oligomeric species human samples control individuals. Detailed analysis revealed decrease Iba1 Low /CD68 robust alterations astrocyte number morphology process retraction. Our data indicated an activation p38/ATF2 signaling pathway mostly induction NF-κB mice. The activity triggered upregulation astrocytic T-type Ca v 3.2 2+ channels, altering secretome promoting secretion IGFBPL1, IGF-1 binding protein anti-inflammatory neuroprotective potential. Conclusions work supports causative link between neuron-produced maps are stimulated astrocytes. also highlights recruitment channels potential mediator against α-synuclein-induced neuroinflammation. Graphical

Language: Английский

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Phytochemical-based therapeutics from traditional eastern medicine: analgesic effects and ion channel modulation

Frontiers in Pain Research, Journal Year: 2025, Volume and Issue: 6

Published: Jan. 31, 2025

Pain management remains a major challenge in the healthcare system. While synthetic analgesics are widely used for pain management, their effectiveness managing chronic is often limited due to low efficacy or side effects. Thus, there growing interest exploring alternative relief methods, particularly using medicinal plants from traditional Eastern medicine and phytochemicals. Previous studies have demonstrated modulatory effects of various phytochemicals derived herbal on pain-related ion channels, such as voltage-gated sodium channels (Nav), calcium (Ca2+), transient receptor potential (TRP) channels. Since these integral transmission modulation signals, ability specific activate inhibit presents promising avenue development novel analgesics. The goal this review merge insights with channel research highlight natural compounds safe effective management. In regard, we summarize discovery characterization pain-relieving medicine, discuss mechanisms action mimic enhance conventional through modulation.

Language: Английский

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Gene therapy for chronic pain: emerging opportunities in target-rich peripheral nociceptors

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(4), P. 252 - 265

Published: Jan. 19, 2023

Language: Английский

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Effect of ABT-639 on Cav3.2 channel activity and its analgesic actions in mouse models of inflammatory and neuropathic pain

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 967, P. 176416 - 176416

Published: Feb. 10, 2024

Language: Английский

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Synthesis, molecular modeling, DFT studies, and EPR analysis of 1,4-dihydropyridines as potential calcium channel blockers

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1307, P. 137983 - 137983

Published: March 7, 2024

Language: Английский

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Marine-derived bioactive compounds for neuropathic pain: pharmacology and therapeutic potential

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Language: Английский

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Entourage effects of non-psychotropic cannabinoids (npCBs) on visceral sensitivity in experimental colitis

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2025, Volume and Issue: 392(3), P. 103389 - 103389

Published: Jan. 17, 2025

Abdominal pain is the most disabling symptom of inflammatory bowel diseases, but current treatments are limited, leading patients to seek alternatives such as cannabis. Cannabis contains over 100 cannabinoids which, unlike tetrahydrocannabinol, biologically active compounds often without psychotropic effects (ie, nonpsychotropic [npCBs]). These npCBs have analgesic and anti-inflammatory properties may show potentiating when administered in combination, referred entourage effect. Here, we investigated cannabichromene, cannabidiol (CBD), cannabidivarin, cannabigerol (CBG), individually using mouse model dextran sulfate sodium colitis-induced visceral hypersensitivity (VHS). We then explored antinociceptive targets through patch-clamp electrophysiology on dorsal root ganglia neurons recombinant channels. found that a single injection 10 mg/kg either CBD or CBG reduced both VHS c-Fos activation spinal horn. Moreover, combination consisting 5 with 1 CBG-all at subtherapeutic dosages-reduced VHS, altering colitis. Electrophysiological recordings revealed mixture acts voltage-gated calcium channels, particularly Cav2.2, not Cav3.2 Kv results suggest CBD, CBG, given doses be beneficial managing associated disease. SIGNIFICANCE STATEMENT: increasingly used an alternative treatment for chronic conditions. Nonpsychotropic cannabinoids, cannabidiol, interact ionotropic ion In our study, demonstrated cannabigerol, doses, effectively alleviated

Language: Английский

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Lentinula edodes mycelia extract abrogates chemotherapy-evoked cold and mechanical allodynia in mice

Future Journal of Pharmaceutical Sciences, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 17, 2025

Abstract Background Chemotherapy-induced peripheral neuropathy (CIPN) is a detrimental outcome of various antineoplastic drugs, such as paclitaxel (PTX), vincristine (VCR), oxaliplatin (L-OHP), and bortezomib (BOR). CIPN results in pain disability, thereby reducing quality life discontinuation chemotherapy. Currently, the only effective treatment for using duloxetine. Therefore, development new treatments necessary. Extract Lentinula edodes mycelia (LEM) improves individuals undergoing chemotherapy treatment. As with LEM may attenuate after chemotherapy, this study was conducted to determine whether abrogates L-OHP-, PTX-, VCR-, BOR-evoked cold mechanical allodynia mice. Results We found that exhibits protective effects against mice treated L-OHP, PTX, VCR, or BOR. also administration BOR elevated mRNA expression Cav3.2, Cav3.3, NR2A DRG mice, whereas abrogated BOR-induced Cav3.2 expression. In addition, ERK1/2 phosphorylation spinal cord Furthermore, reversed symptoms developed receiving Conclusion These findings suggest attenuation phosphorylated ERK1/2, upon be an prophylactic therapeutic strategy allodynia.

Language: Английский

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