Simultaneous assessment of the effects of L-type current modulators on sensory and motor pathways of the mouse spinal cord in vitro

The effects of modulators of L-type currents in the processing of nociceptive stimuli across sensory and motor circuits were studied using an in vitro preparation of the young mouse spinal cord. Responses to repetitive C-fibre intensity stimuli delivered to a lumbar dorsal root were simultaneously recorded from motor axons in the corresponding ventral root and from putative sensory axons in the anterolateral pathway. L-current antagonists verapamil, diltiazem and nimodipine as well as the agonist Bay K8644 were superfused at a range of concentrations and their effects on responses to afferent stimulation were assessed.All antagonists produced a concentration-dependent depression of transmission across sensory and motor pathways by inhibiting sustained firing and wind-up. All antagonists showed concentration-dependent depression of evoked firing in anterolateral fibres with Log IC50 of −4.2 for verapamil, −4.1 for diltiazem and −4.9 for nimodipine. Applied at high concentrations (≥100 μM) verapamil and diltiazem produced almost complete blockade of the ascending signals whereas nimodipine produced only partial depression. The effects of the antagonists on motor pathways were significantly greater and the Log IC50 decreased to −5 for verapamil, to −4.9 for diltiazem and to −5.3 for nimodipine. Bay K8644 applied at 2 μM produced only a slight potentiation of responses in anterolateral axons and a very large and long-lasting potentiation of responses from motor neurons.We conclude that mice motor pathways are more sensitive to L-type current modulators than the anterolateral pathway and that analgesic effects reported for some L-type antagonists may be due to a mixture of selective and non-selective effects of these agents on sensory neurones.