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

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

doi:10.3390/ph15010088

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.

Highlights

The treatment of neuropathic pain remains a tremendous challenge due to its diverse aetiology and complex pathomechanisms, which are still not fully understood
Our findings suggest that several indirect mechanisms may be responsible for mirogabalin’s analgesic action, its interactions with spinal α2δ subunits of calcium channels
We are the first to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the mRNA expression of pronociceptive substance P

Summary

Introduction

The treatment of neuropathic pain remains a tremendous challenge due to its diverse aetiology and complex pathomechanisms, which are still not fully understood. Despite the various therapies available, many patients suffer from ineffective pain relief. Epidemiological studies show that only half of patients can achieve 30–50% pain relief, while the remainder cannot be helped [1]. The search for new and more effective treatments for neuropathic pain continues. First-line drugs in the treatment of this kind of pain include antidepressants (tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors) and gabapentinoids (gabapentin, pregabalin) [1]. A new gabapentinoid recently introduced into clinical practice is mirogabalin

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