title: Positive allosteric modulation of GABA-A receptors reduces capsaicin-induced primary and secondary hypersensitivity in rats.
abstract: GABA-A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain, in part via enhancing injury-induced loss of GABA-A-α2 and -α3 receptor function within the spinal cord. As yet, a lack of clinically suitable tool compounds has prevented this concept being tested in humans. Prior to assessing the efficacy of GABA-A receptor PAMs in a human volunteer pain model we have compared compounds capable of variously modulating GABA-A receptor function in comparable rat models of capsaicin-induced acute nocifensive flinching behaviour and secondary mechanical hypersensitivity. The subtype-selective PAM NS11394 (0.3-10 mg/kg), and the non-selective PAM diazepam (1-5 mg/kg) variously reduced capsaicin-induced secondary mechanical hypersensitivity (180 min post-injection). However, the low efficacy subtype-selective PAM TPA023 (3-30 mg/kg) was completely ineffective. This was surprising as both NS11394 and TPA023 robustly attenuated late phase (6-30 min post-injection) capsaicin-induced flinching, a pain-like behaviour that is putatively driven by peripheral and central sensitizing mechanisms. Diazepam also attenuated capsaicin-induced nocifensive behaviours, albeit at doses previously shown to impair locomotor function. Our data indicate that GABA-A receptor PAMs with optimal selectivity and efficacy profiles reduce centrally-mediated mechanical hypersensitivity in capsaicin-injected rats, an observation that we expect can translate directly to human volunteer studies.
authors.affiliation: Department of Pharmacology, NeuroSearch A/S, Pederstrupvej 93, Ballerup DK-2750, Denmark. rikkeriehansen@gmail.com
authors.forename: Rikke R
authors.initials: RR
authors.lastname: Hansen
authors.forename: Helle K
authors.initials: HK
authors.lastname: Erichsen
authors.forename: David T
authors.initials: DT
authors.lastname: Brown
authors.forename: Naheed R
authors.initials: NR
authors.lastname: Mirza
authors.forename: Gordon
authors.initials: G
authors.lastname: Munro
mesh_terms: D000588:Amines / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D002211:Capsaicin; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D023381:Endpoint Determination; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000737:chemistry* / Q000494:pharmacology*; D000077206:Gabapentin; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D010146:Pain / Q000523:psychology; D010812:Physical Stimulation; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C533864:3'-(5-(1-hydroxy-1-methylethyl)benzoimidazol-1-yl)biphenyl-2-carbonitrile; C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D000588:Amines; D000701:Analgesics, Opioid; D001562:Benzimidazoles; D003509:Cyclohexanecarboxylic Acids; D018756:GABA Antagonists; D018757:GABA Modulators; D011724:Pyridazines; D011963:Receptors, GABA-A; D014230:Triazoles; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D003975:Diazepam; D002211:Capsaicin