PHARMACOLOGICAL PROPERTIES OF T-TYPE CA2-RAT SENSORY NEURONS - EFFECTS OF ANTICONVULSANT AND ANESTHETIC AGENTS( CURRENT IN ADULT)

We have used the whole cell patch-clamp method to study pharmacologica l properties of low-voltage-activated (LVA) Ca2+ current in freshly di ssociated neurons from dorsal root ganglia of adult rats. Inward bariu m current [in the presence of internal fluoride to reduce L-type high- voltage-activated (HVA) and external 1 mu M omega-conotoxin GVIA to bl ock N-type HVA current] was evoked from negative holding potentials of -90 mV to lest potentials of -25 mV and showed complete inactivation during 200-ms test pulses. Amiloride blocked similar to 90% of current with half-maximal block (EC50) of 75 mu M and a Hill coefficient (n) of 0.99. LVA current: was blocked completely by inorganic Ca2+ channel blockers: lanthanum (EC50 = 0.53 mu M) > zinc (EC50 = 11.3 mu M) > ca dmium (EC50 = 20 mu M) > nickel (EC50 = 51 mu M). The antiepileptics, ethosuximide (EC50 = 23.7 mM, n = 1.4), phenytoin (EC50 = 7.3 mu M, n = 1.3), alpha-methyl-alpha-phenylsuccinimide (EC50 = 170 mu M, n = 2.1 ), and valproic acid (EC50 = 330 mu M, n = 1.9) maximally blocked simi lar to 100, 60, 26, and 17% of T current, respectively. Another antiep ileptic, carbamazepine (less than or equal to 100 mu M), and convulsan ts such as pentylenetetrazole (1 mM) and tert-butyl-bicyclo [2.2.2] ph osphorothionate (50 mu M) had no effect on T current. Barbiturates com pletely blocked T current: thiopental (EC50 = 153 mu M, n = 1.2) > pen tobarbital (EC50 = 334 mu M, n = 1.2) > methohexital (EC50 = 502 mu M, n = 1.3) > phenobarbital (EC50 = 1.7 mM, n = 1.2). Blockade by thiope ntal and pentobarbital did not show voltage or use dependence. General anesthetics blocked T current completely and reversibly: propofol (EC 50 = 12.9 mu M, n = 1.3) > octanol (EC50 = 122 mu M, n = 1.2) > etomid ate (EC50 = 205 mu M, n = 1.3) > isoflurane (EC50 = 303 mu M, n = 2.3) > halothane (EC50 = 655 mu M, n = 2.0) > ketamine (EC50 = 2.5 mM, n = 1.1). Mibefradil, a novel Ca2+ channel blocker, blocked dorsal root g anglion T current in a voltage- and use-dependent fashion with an EC50 of similar to 3 mu M (n = 1.3). When compared with results on other T currents, these data indicate that significant differences exist amon g different T currents in terms of pharmacological sensitivities. Furt hermore, differences in pharmacological sensitivity of T currents amon g peripheral neurons, CNS, and neuroendocrine cells may contribute to the spectrum of effects of particular analgesic, anticonvulsant, and a nesthetic drugs.