Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Copyright policy )Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
AbstractAgonists at the benzodiazepine-binding site of GABAA receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABAA receptors (GABAAR). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABAAR point-mutated mice, which express only one benzodiazepine-sensitive GABAAR subtype at a time, to show that targeting only α2GABAARs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain.
- Harvard University United States
- ETH Zurich Switzerland
- École Polytechnique Fédérale de Lausanne EPFL Switzerland
- Institute of Pharmaceutical Sciences Switzerland
- University of Zurich Switzerland
Male, GAMMA-AMINOBUTYRIC ACID RECEPTORS (NEUROLOGY), Midazolam, ANIMAL MODELS IN MEDICINE, 610, 10050 Institute of Pharmacology and Toxicology, Gene Expression, Pain, GAMMA-AMINOBUTTERSÄURE-REZEPTOREN (NEUROLOGIE), 610 Medicine & health, 1600 General Chemistry, BENZODIAZEPINES (HETEROCYCLIC HYDROCARBONS), Arginine, Article, Benzodiazepines, Mice, ANALGETIKA + ANTIPYRETIKA (PHARMAZIE), 1300 General Biochemistry, Genetics and Molecular Biology, Animals, Hypnotics and Sedatives, Pain Management, Point Mutation, Histidine, GABA Modulators, BENZODIAZEPINE (HETEROCYCLISCHE KOHLENWASSERSTOFFE), TIERISCHE MODELLE IN DER MEDIZIN, Medical sciences, medicine, info:eu-repo/classification/ddc/610, Diazepam, Receptors, GABA-A, 3100 General Physics and Astronomy, BENZODIAZEPINES (HETEROCYCLIC HYDROCARBONS); ANIMAL MODELS IN MEDICINE; GAMMA-AMINOBUTYRIC ACID RECEPTORS (NEUROLOGY); ANALGESICS + ANTIPYRETRICS (PHARMACY); ANALGETIKA + ANTIPYRETIKA (PHARMAZIE); TIERISCHE MODELLE IN DER MEDIZIN; GAMMA-AMINOBUTTERSÄURE-REZEPTOREN (NEUROLOGIE); SIDE EFFECTS OF DRUGS + COMPLICATIONS DURING TREATMENT; NEBENWIRKUNGEN VON ARZNEIMITTELN + BEHANDLUNGSKOMPLIKATIONEN; BENZODIAZEPINE (HETEROCYCLISCHE KOHLENWASSERSTOFFE), Spinal Cord, Hyperalgesia, ANALGESICS + ANTIPYRETRICS (PHARMACY), 570 Life sciences; biology, Analgesia, NEBENWIRKUNGEN VON ARZNEIMITTELN + BEHANDLUNGSKOMPLIKATIONEN, SIDE EFFECTS OF DRUGS + COMPLICATIONS DURING TREATMENT
Male, GAMMA-AMINOBUTYRIC ACID RECEPTORS (NEUROLOGY), Midazolam, ANIMAL MODELS IN MEDICINE, 610, 10050 Institute of Pharmacology and Toxicology, Gene Expression, Pain, GAMMA-AMINOBUTTERSÄURE-REZEPTOREN (NEUROLOGIE), 610 Medicine & health, 1600 General Chemistry, BENZODIAZEPINES (HETEROCYCLIC HYDROCARBONS), Arginine, Article, Benzodiazepines, Mice, ANALGETIKA + ANTIPYRETIKA (PHARMAZIE), 1300 General Biochemistry, Genetics and Molecular Biology, Animals, Hypnotics and Sedatives, Pain Management, Point Mutation, Histidine, GABA Modulators, BENZODIAZEPINE (HETEROCYCLISCHE KOHLENWASSERSTOFFE), TIERISCHE MODELLE IN DER MEDIZIN, Medical sciences, medicine, info:eu-repo/classification/ddc/610, Diazepam, Receptors, GABA-A, 3100 General Physics and Astronomy, BENZODIAZEPINES (HETEROCYCLIC HYDROCARBONS); ANIMAL MODELS IN MEDICINE; GAMMA-AMINOBUTYRIC ACID RECEPTORS (NEUROLOGY); ANALGESICS + ANTIPYRETRICS (PHARMACY); ANALGETIKA + ANTIPYRETIKA (PHARMAZIE); TIERISCHE MODELLE IN DER MEDIZIN; GAMMA-AMINOBUTTERSÄURE-REZEPTOREN (NEUROLOGIE); SIDE EFFECTS OF DRUGS + COMPLICATIONS DURING TREATMENT; NEBENWIRKUNGEN VON ARZNEIMITTELN + BEHANDLUNGSKOMPLIKATIONEN; BENZODIAZEPINE (HETEROCYCLISCHE KOHLENWASSERSTOFFE), Spinal Cord, Hyperalgesia, ANALGESICS + ANTIPYRETRICS (PHARMACY), 570 Life sciences; biology, Analgesia, NEBENWIRKUNGEN VON ARZNEIMITTELN + BEHANDLUNGSKOMPLIKATIONEN, SIDE EFFECTS OF DRUGS + COMPLICATIONS DURING TREATMENT
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).92 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!