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

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 a(6)-containing GABA(A) receptor in physiological conditions and neuropathic pain in female and male rats. Results show that a(6)-containing GABA(A) receptor blockade or transient a(6)-containing GABA(A) receptor knockdown induces evoked hypersensitivity and spontaneous pain in naive female rats. The a(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 a(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 a(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 a(6) subunit reduces tactile allodynia and restores a(6) subunit expression in neuropathic rats. Positive allosteric modulators of the a(6)-containing GABA(A) receptor induces a greater antiallodynic effect in female rats and mice compared with male rats and mice. Finally, a(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 a(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.

Automated summary

The loss of GABAergic inhibition contributes to neuropathic pain. Activation of GABA(A) receptors can help reduce neuropathic pain. This study explores the role of the spinal a(6)-containing GABA(A) receptor in neuropathic pain and its potential as a treatment target. Results show that blocking or silencing the a(6)-containing GABA(A) receptor induces hypersensitivity and pain in female rats. The a(6) subunit is expressed in certain neurons and its expression is reduced after nerve injury. Positive allosteric modulators of the a(6)-containing GABA(A) receptor can alleviate allodynia and nociceptive behaviors in female rats. The a(6) subunit is also found in humans. These findings suggest that the spinal a(6)-containing GABA(A) receptor has a sex-specific antinociceptive role and may be a potential target for neuropathic pain treatment.