Actions of the anticonvulsant remacemide metabolite AR-R12495AA on afferent-evoked spinal synaptic transmission in vitro and on models of acute and chronic inflammation in the rat

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-diphenylelhylamine-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 dorsa l root-evoked ventral root potential (DR-VRP) with a slowly decaying phase. Repetitive stimuli (2 Hz) produced summation of slow potentials and a cumu lative ventral root depolarization (CVRD), a form of wind-up. Remacemide an d ARR12495AA antagonized the DR-VRP slow peak t(1/2) decay and slow phase t otal duration at drug concentration of greater than or equal to 25 mu M. AR -R12495AA was approximately 2-fold more potent than remacemide. The most po tent action was against the slow phase duration with IC50 values of 157 and 60 mu M for remacemide and AR-R12495A4, respectively. Both drugs at concen trations of greater than or equal to 100 mu M attenuated the DR-VRP fast pe ak amplitude (IC50 = 253 and 142 mu M, respectively). The amplitude of CVRD was reduced by remacemide and AR-R12495AA (IC50 = 195 and 111 mu M, respec tively). MK-801 reduced DR-VRP fast peak amplitude (IC50 = 58 mu M), slow p eak t(1/2) decay (IC50 = 60 mu M), slow phase duration (IC50 = 50 mu M), an d CVRD amplitude (IC50 = 91 mu M). In behavioral studies, AR-R12495AA (i.p, ) reduced the mechanical hyperalgesia and paw swelling that followed hind p aw injection of carrageenan or Freund's complete adjuvant. These electrophy siological and behavioral data indicate further studies should be conducted on the efficacy of remacemide and AR-R12495AA as putative analgesics.