Abstract

There is evidence that 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) acts as an intracellular Ca++ antagonist producing decreases in free intracellular Ca++ and inhibiting many cellular processes dependent upon intracellular Ca++. Intracerebroventricularly administered TMB-8 was active in the mouse tail-flick test (ED50 = 50 micrograms), and this antinociceptive response was antagonized by naloxone (AD50 = 0.28 mg/kg s.c.), Ca++ (0.2-0.4 mumol i.c.v.) and, to a lesser degree, by ethylene glycol bis (beta-aminoethyl ether)N,N1-tetraacetic acid (0.02 and 0.06 mumol i.c.v.). TMB-8 (i.c.v.) was only marginally active in the p-phenylquinone test. The potency of TMB-8 (i.c.v.) was potentiated 10-fold in morphine-tolerant mice in the tail-flick test (ED50 = 2.5 micrograms). TMB-8 inhibited contraction of stimulated ilea (IC50 = 2.2 microM), an effect which was neither antagonized nor reversed by naloxone (1 microM). TMB-8 did not potentiate morphine, or was it potentiated by morphine, in the stimulated guinea pig ileum. Procaine, but not lidocaine showed dose-dependent activity in the tail-flick and p-phenylquinone tests (ED50 values, 136 and 83 micrograms, respectively, i.c.v.). The antinociception produced by procaine (i.c.v.) in the tail-flick test was antagonized by naloxone (AD50 = 0.4 mg/kg s.c.) Lidocaine (100 micrograms i.c.v.) produced only 30% maximum possible effect in the tail-flick tests, and was inactive in p-phenylquinone tests. Doses of lidocaine greater than 100 micrograms i.c.v. resulted in lethality of greater than 50% of the animals tested. Thus, the activity of TMB-8 resembles that of opiates in that both are antagonized by Ca++ or naloxone in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)