Mirogabalin and pregabalin alleviate nociplastic sensitization induced by chemogenetic activation of the central amygdala neurons in rodents

Abstract

Nociplastic pain represents the third mechanistic descriptor of pain, alongside neuropathic and nociceptive pain, as proposed in 2017 by the International Association for the Study of Pain (IASP). It describes pain occurring in the absence of nociceptor activation, tissue damage, or neuropathy. The underlying brain mechanisms of nociplastic pain remain poorly understood. Despite the potentially large patient population with chronic pain of this class, effective pharmacological treatments for nociplastic pain are still limited, highlighting the urgent need for drug development using appropriate preclinical models. In this study, we investigated the anti-sensitization effects of two gabapentinoids-mirogabalin besylate (MGB) and pregabalin (PGB)-using a rodent model of nociplastic pain. This model involves experimental excitation of central amygdala neurons via designer receptors exclusively activated by designer drugs (DREADDs), causing widespread sensitization. Administration of an artificial ligand, deschloroclozapine (DCZ; 0.1 mg/kg, i.p.), significantly reduced the 50 %-paw withdrawal threshold, which was significantly elevated by MGB (10 mg/kg, i.p.) and PGB (30 mg/kg, i.p.), restoring it to levels not significantly different from the pre-DCZ baseline. We conclude that MGB and PGB alleviate widespread sensitization in this nociplastic pain model, likely through their action on α₂δ-1 subunits within brain circuits that regulate pain sensitivity.

Keywords: Chemogenetics; Nociplastic pain; Sensitization; VGAT-Cre rat; α(2)δ-1 subunit.