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Papers of the Week

Papers: 20 Aug 2022 - 26 Aug 2022

Pharmacology/Drug Development

2022 Aug 24


Activation of α6-containing GABAA receptors induces antinociception under physiological and pathological conditions.


Rodríguez-Palma EJ, De la Luz-Cuellar YE, Islas-Espinoza AM, Félix-Leyva AE, Shiers SI, García G, Torres-Lopez JE, Delgado-Lezama R, Murbartián J, Price TJ, Granados-Soto V
Pain. 2022 Aug 24.
PMID: 36001074.


The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through activation of GABAA receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α6-containing GABAA receptor in physiological conditions and neuropathic pain in female and male rats. Results show that α6-containing GABAA receptor blockade or transient α6-containing GABAA receptor knockdown induces evoked hypersensitivity and spontaneous pain in naïve female rats. The α6 subunit is expressed in IB4+ and CGRP+ primary afferent neurons in the rat spinal dorsal horn and dorsal root ganglia (DRG), but not astrocytes. Nerve injury reduces α6 subunit protein expression in the central terminals of the primary afferent neurons and DRG, whereas intrathecal administration of positive allosteric modulators (PAMs) of the α6-containing GABAA receptor reduces tactile allodynia and spontaneous nociceptive behaviors in female, but not male, neuropathic rats and mice. Overexpression of the spinal α6 subunit reduces tactile allodynia and restores α6 subunit expression in neuropathic rats. PAMs of the α6-containing GABAA receptor induces a greater antiallodynic effect in females compared to male rats and mice. Finally, α6 subunit is expressed in humans. This receptor is found in CGRP+ and P2X3+ primary afferent fibers but not astrocytes in the human spinal dorsal horn. Our results suggest that the spinal α6-containing GABAA receptor has a sex-specific antinociceptive role in neuropathic pain, suggesting that this receptor may represent an interesting target to develop a novel treatment for neuropathic pain.