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

被引:29
作者
Garcia de Lucas, A. [1 ]
Ahring, P. K. [2 ,3 ]
Larsen, J. S. [2 ]
Rivera-Arconada, I. [1 ]
Lopez-Garcia, J. A. [1 ]
Mirza, N. R. [2 ]
Munro, G. [4 ]
机构
[1] Univ Alcala, Dept Physiol, Madrid, Spain
[2] Saniona AB, DK-2750 Ballerup, Denmark
[3] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia
[4] NeuroSearch AS, Dept Pharmacol, DK-2750 Ballerup, Denmark
关键词
Analgesia; Central sensitization; Hyperalgesia; Pain; Spinal inhibition; Wind-up; DORSAL-HORN; PATHOLOGICAL PAIN; RAT MODELS; IN-VITRO; AGONIST; DIAZEPAM; LORAZEPAM; SUBTYPES; CORD; HYPERSENSITIVITY;
D O I
10.1016/j.bcp.2014.12.010
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
GABA(A) receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABA(A)-alpha 2 and -alpha 3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABA(A)-alpha 5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABA(A)-alpha 2/ alpha 3/alpha 5 receptors) with TP003 (a reportedly GABA(A)-alpha 3 selective PAM) against spinal sensitization. However, in-house electrophysiology studies designed to confirm the selectivity of TPA023 and TP003 for human GABA(A) receptors did not corroborate published data, with TP003 displaying considerable GABA(A)-alpha 5 receptor efficacy. Therefore, we identified a novel PAM, NS16085, which possesses negligible efficacy at GABA(A)-alpha 5 receptors, but with GABA(A)-alpha 2/alpha 3 efficacy equivalent to NS11394. At the GABA(A)-alpha 1 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 GABA(A)-alpha 2 and-alpha 3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABA(A)-alpha 5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:370 / 379
页数:10
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