ns-11394 and Pain

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.

Topics: Amines; Analgesics, Opioid; Animals; Behavior, Animal; Benzimidazoles; Capsaicin; Cyclohexanecarboxylic Acids; Diazepam; Endpoint Determination; GABA Antagonists; GABA Modulators; Gabapentin; gamma-Aminobutyric Acid; Hyperalgesia; Male; Pain; Physical Stimulation; Pyridazines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Triazoles

The aim of the present paper was to study the effects of GABAA receptor-positive modulators (L-838417 and NS11394) showing a preference for α2/3 subunits of the GABAA receptor, in models of pain, anxiety, learning, memory and motor function. These compounds have been suggested to have a favourable therapeutic profile over nonselective compounds such as diazepam. In this study, we tested both compounds for their effects in rat models of formalin-induced pain, spinal nerve-ligation-induced mechanical allodynia, plus maze, open field, rotarod, balance beam walking, contextual fear conditioning and Morris water maze. Both compounds exerted analgesic, but no anxiolytic effects. However, they induced motor side-effects, and learning and memory impairment at similar doses. Therefore, the anxiolytic effect and the lack of side-effects of these compounds, as described in the literature, could not be confirmed in the present study.

Topics: Allosteric Regulation; Analgesics; Animals; Anxiety; Benzimidazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Fluorobenzenes; GABA-A Receptor Agonists; Male; Maze Learning; Memory Disorders; Motor Activity; Pain; Rats; Rats, Wistar; Receptors, GABA-A; Triazoles