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

Laetitia Tudeau; Mario A Acuña; Gioele W Albisetti; Elena Neumann; William T Ralvenius; Louis Scheurer; Michael Poe; James M Cook; Helge C Johannssen; Hanns Ulrich Zeilhofer

doi:10.1016/j.brainres.2020.146889

Mice lacking spinal α2GABA_A receptors: Altered GABAergic neurotransmission, diminished GABAergic antihyperalgesia, and potential compensatory mechanisms preventing a hyperalgesic phenotype

Brain Res. 2020 Aug 15:1741:146889. doi: 10.1016/j.brainres.2020.146889. Epub 2020 May 18.

Affiliations

¹ Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland.
² Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, USA.
³ Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, CH-8093 Zurich, Switzerland. Electronic address: zeilhofer@pharma.uzh.ch.

PMID: 32439345
DOI: 10.1016/j.brainres.2020.146889

Abstract

Diminished synaptic inhibition in the superficial spinal dorsal horn contributes to exaggerated pain responses that accompany peripheral inflammation and neuropathy. α2GABA_A receptors (α2GABA_AR) constitute the most abundant GABA_AR subtype at this site and are the targets of recently identified antihyperalgesic compounds. Surprisingly, hoxb8-α2^-/- mice that lack α2GABA_AR 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-α2^-/- mice. Our results confirm that hoxb8-α2^-/- 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 α2-preferring GABA_AR modulator HZ-166 is reduced in hoxb8-α2^-/- mice and that hoxb8-α2^-/- 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-α2^-/- mice rendering a compensatory up-regulation of other GABA_AR 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-α2^-/- 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 α2GABA_AR to spinal nociceptive control but their ablation early in development appears to activate yet-to-be identified compensatory mechanisms that protect hoxb8-α2^-/- mice from hyperalgesia.

Keywords: Benzodiazepine; Disinhibition; GABA; Glycine; Mouse mutant; Pain; Spinal cord.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
GABAergic Neurons / metabolism*
HEK293 Cells
Humans
Hyperalgesia / genetics
Hyperalgesia / metabolism*
Inhibitory Postsynaptic Potentials / physiology
Male
Mice
Mice, Transgenic
Organ Culture Techniques
Phenotype*
Receptors, GABA-A / deficiency*
Receptors, GABA-A / genetics
Spinal Cord / metabolism*
Synaptic Transmission / physiology*

Substances

Gabrr2 protein, mouse
Receptors, GABA-A