α6GABAA receptor-selective positive allosteric modulator as a novel therapy for fibromyalgia: A proof-of-concept study in mice modeling chronic widespread musculoskeletal pain

Key Findings

Fibromyalgia, a chronic pain disorder mainly due to central sensitization, remains an unmet medical need, as available treatments provide limited efficacy and are frequently associated with dose-limiting adverse effects. We previously developed pyrazoloquinolinone (PQ) compounds as the first positive allosteric modulators that selectively bind to GABAA receptors containing the α6 subunit (α6GABAARs), among others. Here, we found that PQ Compound 6 and its deuterated, druggable candidate, DK-I-56-1, alleviated mechanical allodynia and thermal hyperalgesia in fibromyalgia models induced by dual acidic-saline injections and intermittent cold stress in ICR mice. The antinociceptive effects of PQs were sexually dimorphic, with greater sensitivity in females, and did not develop tolerance after repeated administrations. Moreover, their antinociceptive effects were prevented by furosemide, an α6GABAAR antagonist, administered by intrathecal, but not systemic, injection, and were abolished in Gabra6 (the α6 subunit-encoding gene)-knockout mice, suggesting the involvement of spinal α6GABAARs. Immunofluorescent staining supports the presence of α6GABAARs in the spinal dorsal horn and co-localization with NeuN. DK-I-56-1 produced anti-nociceptive efficacy (10 mg/kg in males and 3 mg/kg in females) comparable to gabapentin (10 mg/kg) following i.p. administration, and exhibited an additive effect with gabapentin when co-administered at low doses. These results suggest that the α6GABAAR-selective positive allosteric modulator, such as DK-I-56-1, is a potential strategy for fibromyalgia pain management as monotherapy or as adjuncts to gabapentinoids.

Why This Matters for Body-Mind Practice

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Source

• α6GABAA receptor-selective positive allosteric modulator as a novel therapy for fibromyalgia: A proof-of-concept study in mice modeling chronic widespread musculoskeletal pain. — Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics