Peer-Reviewed Journal Details
Mandatory Fields
Munro, G;Erichsen, HK;Rae, MG;Mirza, NR
2011
July
Neuropharmacology
A question of balance - Positive versus negative allosteric modulation of GABA(A) receptor subtypes as a driver of analgesic efficacy in rat models of inflammatory and neuropathic pain
Validated
WOS: 38 ()
Optional Fields
CATION-CHLORIDE-COTRANSPORTERS NERVE INJURY MODEL INVERSE AGONIST PRESYNAPTIC INHIBITION COGNITIVE FUNCTION ANIMAL-MODELS HYPERALGESIA MORPHINE DIAZEPAM NEURONS
61
121
132
After injury GABA(A) receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABA(A)-alpha 2 and -alpha 3 receptor function within the spinal cord. GABA can also act at GABAA receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABAA receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1-10 mg/kg) and TPA023 (3-30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenan-inflamed and nerve-injured rats. The non-selective PAM diazepam (1-5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3-30 mg/kg) and the alpha 5-selective NAM alpha 51A-II (10-60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenan-inflamed rats alpha 5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of N511394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABA(A) receptors might be more complex than previously anticipated, and is worthy of further exploration. (C) 2011 Elsevier Ltd. All rights reserved.
OXFORD
0028-3908
10.1016/j.neuropharm.2011.03.017
Grant Details