Lignocaine selectively reduces C fibre-evoked neuronal activity in rat spinal cord in vitro by decreasing N-methyl-D-aspartate and neurokinin receptor-mediated post-synaptic depolarizations; implications for the development of novel centrally acting analgesics.
The action of lignocaine on nociceptive transmission in the spinal cord has been studied in vitro using ventral root potential (VRP) recordings from 10-12-day-old rat hemisected spinal cord preparations. Single-shock stimulation of a dorsal root at intensities sufficient to activate high-threshold C-primary afferent fibres elicited VRPs lasting for 15-20 sec in the corresponding ventral root. The VRP consisted of 3 distinct parts: the early, slow and prolonged components, as previously described (Thompson et al. 1992), where the early represents A beta fibre-evoked mono- and polysynaptic responses lasting for tens of milliseconds, the slow is a largely N-methyl-D-aspartic acid (NMDA) receptor-mediated small-calibre afferent-generated component, lasting for about 1.5 sec, and the prolonged is a neurokinin receptor-mediated long-lasting component generated by high-threshold fibres. Lignocaine superfusion (40-60 microM) significantly and reversibly reduced the slow and prolonged components of the C fibre-evoked VRP in a dose-dependent manner without any effect on the early or A beta fibre-mediated component of the VRP. The amplitude of the cumulative VRP generated by repetitive inputs (1 and 10 Hz) was also significantly reduced as was the depolarization produced by bath application of NMDA (100 microM) or substance P (SP, 1 microM) in the presence or absence of tetrodotoxin (TTX) (300 nM). At this dose range lignocaine had no effect on the compound action potential (CAP) elicited by stimulating the sciatic nerve and recorded on the dorsal root. The CAP was only significantly reduced with a 300 microM dose of lignocaine. Application of the opiate, glycine, GABAA and GABAB receptor antagonists, naloxone (1 microM), strychnine (100 microM), bicuculline (100 microM) and phaclofen (100 microM) did not alter the depressant effects of lignocaine on the VRP. Low concentrations of lignocaine have a selective action on nociceptive transmission in the spinal cord which is different and more potent than its local anaesthetic conduction blockade in the periphery. This includes a reduction of direct or synaptically driven NMDA- and NK receptor-mediated post-synaptic depolarizations indicating that this class of sodium channel blockers may be potentially useful as analgesic agents, possibly acting on TTX-resistant sodium ion channels.
Nagy
Istvan
I
Department of Anatomy and Developmental Biology, University College London, Gower Street, London WCIE 6BT UK.
Woolf
Clifford J
CJ
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D004594:Electrophysiology; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology*; D009412:Nerve Fibers / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
D000700:Analgesics; D016194:Receptors, N-Methyl-D-Aspartate; D008012:Lidocaine