Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain

Zajączkowska, Renata; Rojewska, Ewelina; Ciechanowska, A; Pawlik, Katarzyna; Ciapała, Katarzyna; Kocot-Kępska, Magdalena; Makuch, Wioletta; Wordliczek, Jerzy; Mika, Joanna

doi:10.3390/ph15010088

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…With this feeding assay, we found that gabapentin, an analgesic administered for neuropathic pain [ 40 , 43 , 61 , 62 ], also reduced the elicited pain in the flies. Gabapentin works through inhibiting the α 2 δ-subunit of VGCCs, which is essential to synaptic transmission [ 40 , 63 – 65 ].…”

Section: Discussionmentioning

confidence: 99%

Drosophila pain sensitization and modulation unveiled by a novel pain model and analgesic drugs

Jang

Cho

et al. 2023

PLoS ONE

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In mammals, pain is regulated by the combination of an ascending stimulating and descending inhibitory pain pathway. It remains an intriguing question whether such pain pathways are of ancient origin and conserved in invertebrates. Here we report a new Drosophila pain model and use it to elucidate the pain pathways present in flies. The model employs transgenic flies expressing the human capsaicin receptor TRPV1 in sensory nociceptor neurons, which innervate the whole fly body, including the mouth. Upon capsaicin sipping, the flies abruptly displayed pain-related behaviors such as running away, scurrying around, rubbing vigorously, and pulling at their mouth parts, suggesting that capsaicin stimulated nociceptors in the mouth via activating TRPV1. When reared on capsaicin-containing food, the animals died of starvation, demonstrating the degree of pain experienced. This death rate was reduced by treatment both with NSAIDs and gabapentin, analgesics that inhibit the sensitized ascending pain pathway, and with antidepressants, GABAergic agonists, and morphine, analgesics that strengthen the descending inhibitory pathway. Our results suggest Drosophila to possess intricate pain sensitization and modulation mechanisms similar to mammals, and we propose that this simple, non-invasive feeding assay has utility for high-throughput evaluation and screening of analgesic compounds.

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Section: Discussionmentioning

confidence: 99%

Drosophila pain sensitization and modulation unveiled by a novel pain model and analgesic drugs

Jang

Cho

et al. 2023

PLoS ONE

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“…The following drugs were used in the present study: mirogabalin (M; 10, 20, 40 mg/kg, MedChemExpress, Monmouth Junction, USA), and pregabalin (10, 20, 40 mg/kg, Pfizer Inc., New York, NY, USA). The scheme of the experiments and dosages used in our current study were based on our previously published papers [ 55 , 56 , 57 ]. The drugs were dissolved in aqua pro-injection and administered intraperitoneally (i.p.).…”

Section: Methodsmentioning

confidence: 99%

Mirogabalin Decreases Pain-like Behaviors by Inhibiting the Microglial/Macrophage Activation, p38MAPK Signaling, and Pronociceptive CCL2 and CCL5 Release in a Mouse Model of Neuropathic Pain

et al. 2023

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Neuropathic pain is a chronic condition that significantly reduces the quality of life of many patients as a result of ineffective pain relief therapy. For that reason, looking for new analgesics remains an important issue. Mirogabalin is a new gabapentinoid that is a specific ligand for the α2σ-1 and α2σ-2 subunits of voltage-gated calcium channels. In the present study, we compared the analgesic effect of pregabalin and mirogabalin in a neuropathic pain chronic constriction injury (CCI) of the sciatic nerve in a mouse model. The main purpose of our study was to determine the effectiveness of mirogabalin administered both once and repeatedly and to explain how the drug influences highly activated cells at the spinal cord level in neuropathy. We also sought to understand whether mirogabalin modulates the selected intracellular pathways (p38MAPK, ERK, JNK) and chemokines (CCL2, CCL5) important for nociceptive transmission, which is crucial information from a clinical perspective. First, our study provides evidence that a single mirogabalin administration diminishes tactile hypersensitivity more effectively than pregabalin. Second, research shows that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This study reports that repeated intraperitoneally (i.p.) mirogabalin administration strongly prevents spinal microglia/macrophage activation evoked by nerve injury, slightly suppresses astroglia and neutrophil infiltration, and reduces the p38MAPK levels associated with neuropathic pain, as measured on Day 7. Moreover, mirogabalin strongly diminished the levels of the pronociceptive chemokines CCL2 and CCL5. Our results indicate that mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

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Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice

Sałat,

Zaręba,

Awtoniuk

et al. 2023

Molecules

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Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. Methods: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. Results: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. Conclusions: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics.

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Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain

Cited by 3 publications

References 52 publications

Drosophila pain sensitization and modulation unveiled by a novel pain model and analgesic drugs

Drosophila pain sensitization and modulation unveiled by a novel pain model and analgesic drugs

Mirogabalin Decreases Pain-like Behaviors by Inhibiting the Microglial/Macrophage Activation, p38MAPK Signaling, and Pronociceptive CCL2 and CCL5 Release in a Mouse Model of Neuropathic Pain

Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice

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