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

Abstract

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

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

“…In the mouse STZ-induced model of diabetic neuropathic pain, we confirmed that mirogabalin used at the dose of 30 mg/kg was able to elevate the mechanical and heat nociceptive threshold. This finding is in line with the previously reported data from diabetic patients (e.g., [26,29]) and some limited data about its preclinical efficacy in rodent models of diabetic peripheral neuropathy (e.g., [42]), as well as chronic constriction injury [43] and spinal cord injury [44] animal models. In our research, a lower dose of mirogabalin (10 mg/kg) compared to STZ-treated control was also able to attenuate tactile allodynia in diabetic neuropathic mice but this dose did not affect the heat nociceptive threshold.…”

“…Cebranopadol at the dose of 10 mg/kg was injected subcutaneously. The doses of mirogabalin and cebranopadol were selected based on the previous studies [17] and the available literature data [67]. Control animals were given an appropriate amount of vehicle (1% Tween 80).…”

“…To sum up, our present research was the first one that was focused on the investigation of effects of mirogabalin and cebranopadol on pain responses of paclitaxel and oxaliplatinexposed mice. We focused on studying animals' behavioral responses and we did not assess the impact of mirogabalin or cebranopadol on various molecular targets implicated in chronic pain development: receptors, ion channels and cells implicated in pain processing (e.g., VGCCs, transporters, chemokines and microglia), as such analyses are relatively well-described in the literature (e.g., [3,7,43,[76][77][78]).…”

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

“…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 ].…”

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

“…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.).…”