Mice lacking spinal α2GABAA receptors: Altered GABAergic neurotransmission, diminished GABAergic antihyperalgesia, and potential compensatory mechanisms preventing a hyperalgesic phenotype

Diminished synaptic inhibition in the superficial spinal dorsal horn contributes to exaggerated pain responses that accompany peripheral inflammation and neuropathy. alpha 2GABA(A) receptors (alpha 2GABA(A)R) constitute the most abundant GABA(A)R subtype at this site and are the targets of recently identified antihyperalgesic compounds. Surprisingly, hoxb8-alpha 2(-/-) mice that lack alpha 2GABA(A)R from the spinal cord and peripheral sensory neurons exhibit unaltered sensitivity to acute painful stimuli and develop normal inflammatory and neuropathic hyperalgesia. Here, we provide a comprehensive analysis of GABAergic neurotransmission, of behavioral phenotypes and of possible compensatory mechanisms in hoxb8-alpha 2(-/-) mice. Our results confirm that hoxb8-alpha 2(-/-) mice show significantly diminished GABAergic inhibitory postsynaptic currents (IPSCs) in the superficial dorsal horn but no hyperalgesic phenotype. We also confirm that the potentiation of dorsal horn GABAergic IPSCs by the alpha 2-preferring GABA(A)R modulator HZ-166 is reduced in hoxb8-alpha 2(-/-) mice and that hoxb8-alpha 2(-/-) mice are resistant to the analgesic effects of HZ-166. Tonic GABAergic currents, glycinergic IPSCs, and sensory afferent-evoked EPSCs did not show significant changes in hoxb8-alpha 2(-/-) mice rendering a compensatory up-regulation of other GABA(A)R subtypes or of glycine receptors unlikely. Although expression of serotonin and of the serotonin producing enzyme tryptophan hydroxylase (TPH2) was significantly increased in the dorsal horn of hoxb8-alpha 2(-/-) mice, ablation of serotonergic terminals from the lumbar spinal cord failed to unmask a nociceptive phenotype. Our results are consistent with an important contribution of alpha 2GABA(A)R to spinal nociceptive control but their ablation early in development appears to activate yet-to-be identified compensatory mechanisms that protect hoxb8-alpha 2(-/-) mice from hyperalgesia.