1. Activation of α 6 -containing GABA A receptors induces antinociception under physiological and pathological conditions.
- Author
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Rodríguez-Palma EJ, De la Luz-Cuellar YE, Islas-Espinoza AM, Félix-Leyva AE, Shiers SI, García G, Torres-López JE, Delgado-Lezama R, Murbartián J, Price TJ, and Granados-Soto V
- Subjects
- Male, Rats, Female, Mice, Humans, Animals, Hyperalgesia, Calcitonin Gene-Related Peptide metabolism, Spinal Cord Dorsal Horn metabolism, Receptors, GABA-A metabolism, Neuralgia
- Abstract
Abstract: The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through the activation of GABA A receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α 6 -containing GABA A receptor in physiological conditions and neuropathic pain in female and male rats. Results show that α 6 -containing GABA A receptor blockade or transient α 6 -containing GABA A receptor knockdown induces evoked hypersensitivity and spontaneous pain in naive female rats. The α 6 subunit is expressed in IB4 + and CGRP + primary afferent neurons in the rat spinal dorsal horn and dorsal root ganglia but not astrocytes. Nerve injury reduces α 6 subunit protein expression in the central terminals of the primary afferent neurons and dorsal root ganglia, whereas intrathecal administration of positive allosteric modulators of the α 6 -containing GABA A receptor reduces tactile allodynia and spontaneous nociceptive behaviors in female, but not male, neuropathic rats and mice. Overexpression of the spinal α 6 subunit reduces tactile allodynia and restores α 6 subunit expression in neuropathic rats. Positive allosteric modulators of the α 6 -containing GABA A receptor induces a greater antiallodynic effect in female rats and mice compared with male rats and mice. Finally, α 6 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 α 6 -containing GABA A 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., (Copyright © 2022 International Association for the Study of Pain.)
- Published
- 2023
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