title: GABAA α5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085.
abstract: GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABAA-α2 and -α3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABAA-α5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABAA-α2/α3/α5 receptors) with TP003 (a reportedly GABAA-α3 selective PAM) against spinal sensitization. However, in-house electrophysiology studies designed to confirm the selectivity of TPA023 and TP003 for human GABAA receptors did not corroborate published data, with TP003 displaying considerable GABAA-α5 receptor efficacy. Therefore, we identified a novel PAM, NS16085, which possesses negligible efficacy at GABAA-α5 receptors, but with GABAA-α2/α3 efficacy equivalent to NS11394. At the GABAA-α1 receptor the compound gives low level of negative modulation further separating it from the other compounds. Rat pups with carrageenan-induced hindpaw inflammatory hyperalgesia were used to make ex vivo spinal dorsal root-evoked ventral root recordings. Some spontaneous activity and large numbers of spikes to repetitive stimulation of dorsal roots at C-fibre intensity, indicative of wind-up and sensitization were observed. Equimolar concentrations of NS11394, TP003 and NS16085 all attenuated wind-up to a similar degree; TPA023 was clearly less effective. In adult rats, NS16085 (3-30 mg/kg, p.o.) dose-dependently reduced formalin-induced hindpaw flinching with efficacy comparable to NS11394. Thus, potentiation of GABAA-α2 and-α3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABAA-α5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function.
authors.affiliation: Department of Physiology, University of Alcala, Alcala de Henares, Madrid, Spain.
authors.forename: A Garcia
authors.initials: AG
authors.lastname: de Lucas
authors.affiliation: Saniona AB, Baltorpvej 154, Ballerup DK-2750, Denmark; Faculty of Pharmacy, The University of Sydney, Australia.
authors.forename: P K
authors.initials: PK
authors.lastname: Ahring
authors.affiliation: Saniona AB, Baltorpvej 154, Ballerup DK-2750, Denmark.
authors.forename: J S
authors.initials: JS
authors.lastname: Larsen
authors.affiliation: Department of Physiology, University of Alcala, Alcala de Henares, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Rivera-Arconada
authors.affiliation: Department of Physiology, University of Alcala, Alcala de Henares, Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Lopez-Garcia
authors.affiliation: Saniona AB, Baltorpvej 154, Ballerup DK-2750, Denmark.
authors.forename: N R
authors.initials: NR
authors.lastname: Mirza
authors.affiliation: Department of Pharmacology, NeuroSearch A/S, Pederstrupvej 93, Ballerup DK-2750, Denmark. Electronic address: gmun@lundbeck.com.
authors.forename: G
authors.initials: G
authors.lastname: Munro
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D018757:GABA Modulators / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009924:Organ Culture Techniques; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D013126:Spinal Nerve Roots / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D014982:Xenopus laevis
chemical_list: C000596979:4-chloro-3-(6-(5-(2-hydroxypropan-2-yl)-1H-1,3-benzodiazol-1-yl)pyridin-2-yl)benzonitrile; D001562:Benzimidazoles; D018757:GABA Modulators; C527986:GABRA5 protein, human; D011725:Pyridines; D011963:Receptors, GABA-A
keywords: Analgesia; Central sensitization; Hyperalgesia; Pain; Spinal inhibition; Wind-up