Abstract| Volume 14, ISSUE 4, SUPPLEMENT , S69, April 2013

NP260, a novel GABA-A receptor antagonist, dampens neuronal hyperexcitability and relieves mechanical allodynia in a rat model of neuropathic pain

      We have identified a series of compounds that facilitate inhibitory neurotransmission and show analgesic activity through a novel mechanism. Oral dosing of one such compound, NP260 (15 – 100 mg/kg, 5 days, B.I.D.) to rats with spinal nerve ligation (SNL – Chung model) significantly reduced mechanical allodynia in a dose-dependent fashion on each day of behavioral evaluation. Tests 4 hours after the first dose increased the paw withdrawal threshold (PWT) from 2.5 ± 0.4g in vehicle treated animals to 3.8 ± 0.5 g in animals treated with 15 mg/kg NP260 (n = 8, P < 0.05, ANOVA). The same test on day 5 of chronic dosing generated PWTs of 2.2 ± 0.2 g in vehicle animals and 5.2 ± 0.8 g in the 15 mg/kg NP260 group (P < 0.05, ANOVA). In follow-up electrophysiology studies, acutely dissociated L4-L6 dorsal root ganglion (DRG) neurons, both contralateral and ipsilateral to the site of SNL surgery, exhibited robust GABA-evoked currents that were blocked by 10 μM NP260. NP260 also hyperpolarized the resting membrane potential of these neurons and increased the rheobase needed to elicit action potential firing. In longitudinal spinal cord slices, 10 μM NP260 reduced the amplitude of evoked EPSCs (71.4 ± 5.5% of control, P < 0.001, n=19), decreased the frequency (41.9 ± 4.4% of control, P < 0.03, n=8) and amplitude (58.9 ± 4.4% of control, P < 0.05, n=3) of spontaneous EPSCs, and increased the frequency of spontaneous IPSCs (182.9 ± 6.8% of control, P < 0.001, n=7) in lamina I/II neurons. In each case, the effect of NP260 was notably larger in neurons on the ipsilateral side compared to the contralateral side. Studies are ongoing to further investigate the electrophysiological actions of our compounds and determine their efficacy after chronic oral dosing in animals with neuropathy induced by oxaliplatin. Support provided by NeuroTherapeutics Pharma Inc.