title: Restoring the spinal pain gate: GABA(A) receptors as targets for novel analgesics.
abstract: GABAA receptors (GABA(A)Rs) and glycine receptors are key elements of the spinal control of nociception and pain. Compromised functioning of these two transmitter systems contributes to chronic pain states. Restoring their proper function through positive allosteric modulators should constitute a rational approach to the treatment of chronic pain syndromes involving diminished inhibitory spinal pain control. Although classical benzodiazepines (i.e., full agonists at the benzodiazepine binding site of GABA(A)Rs) potentiate synaptic inhibition in spinal pain controlling circuits, they lack clinically relevant analgesic activity in humans. Recent data obtained from experiments in GABA(A)R point-mutated mice suggests dose-limiting sedative effects of classical nonspecific benzodiazepines as the underlying cause. Experiments in genetically engineered mice resistant to the sedative effects of classical benzodiazepines and studies with novel less sedating benzodiazepines have indeed shown that profound antihyperalgesia can be obtained at least in preclinical pain models. Present evidence suggests that compounds with high intrinsic activity at α2-GABA(A)R and minimal agonistic activity at α1-GABA(A)R should possess relevant antihyperalgesic activity without causing unwanted sedation. On-going preclinical studies in genetically engineered mice and clinical trials with more selective benzodiazepine site agonists should soon provide additional insights into this emerging topic.
authors: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich, Zurich, Switzerland. Electronic address: zeilhofer@pharma.uzh.ch.
authors: Hanns Ulrich
authors: HU
authors: Zeilhofer
authors: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors: William T
authors: WT
authors: Ralvenius
authors: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors: Mario A
authors: MA
authors: Acuña
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000700:Analgesics; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines
keywords: Allodynia; Diazepam; Gate-control-theory; Hyperalgesia; Knock-in; Neuropathy; Pain; Point mutation; Spinal cord