Abstract

The effects of the anticonvulsant remacemide [(±)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its metabolite AR-R12495AA [(±)-1-methyl-1,2-diphenylethylamine-monohydrochloride] on primary afferent synaptic transmission were assessed in the young rat spinal cord in vitro. Stimulation of dorsal roots at A- and C-afferent intensity elicited a dorsal root-evoked ventral root potential (DR-VRP) with a slowly decaying phase. Repetitive stimuli (2 Hz) produced summation of slow potentials and a cumulative ventral root depolarization (CVRD), a form of wind-up. Remacemide and AR-R12495AA antagonized the DR-VRP slow peak t_1/2 decay and slow phase total duration at drug concentration of ≥25 μM. AR-R12495AA was approximately 2-fold more potent than remacemide. The most potent action was against the slow phase duration with IC₅₀ values of 157 and 60 μM for remacemide and AR-R12495AA, respectively. Both drugs at concentrations of ≥100 μM attenuated the DR-VRP fast peak amplitude (IC₅₀ = 253 and 142 μM, respectively). The amplitude of CVRD was reduced by remacemide and AR-R12495AA (IC₅₀ = 195 and 111 μM, respectively). MK-801 reduced DR-VRP fast peak amplitude (IC₅₀ = 58 μM), slow peakt_1/2 decay (IC₅₀ = 60 μM), slow phase duration (IC₅₀ = 50 μM), and CVRD amplitude (IC₅₀ = 91 μM). In behavioral studies, AR-R12495AA (i.p.) reduced the mechanical hyperalgesia and paw swelling that followed hind paw injection of carrageenan or Freund's complete adjuvant. These electrophysiological and behavioral data indicate further studies should be conducted on the efficacy of remacemide and AR-R12495AA as putative analgesics.