Research ReportM-channels modulate network excitatory activity induced by 4-aminopyridine in immature rat substantia gelatinosa in vitro

- M-current modulation altered 4-AP excitations in rat substantia gelatinosa in vitro.
- M-current activators Retigabine and Flupirtine depressed 4-AP-induced excitations.
- M-current blockers XE911 and Linopirdine enhanced 4-AP-induced excitations.
- Central actions may enhance anti-nociceptive potency of M-current analgesics.

There is strong evidence that M-currents modulate peripheral sensory afferent excitability and that altered M-current efficacy may underpin aspects of pain-induced nociceptor sensitization. Less clear is the role of the M-current in regulating central excitability within spinal dorsal horn nociceptive circuitry. In this study, an in vitro model of central hyperexcitability that uses the potassium channel blocker 4-aminopyridine (4-AP) to induce large amplitude population spikes and 4-12 Hz oscillatory activity within rat spinal substantia gelatinosa (SG) has been used to determine the impact of pharmacological modulation of the M-current on central excitability. The M-current enhancers Retigabine (10 and 30 μM) and Flupirtine (30 μM) had a depressant effect on 4-AP-induced excitation in SG such that the frequency of large amplitude population spikes and the power of 4-12 Hz oscillatory activity were both significantly reduced. In contrast, the M-current blockers XE911 (5 μM) or Linopirdine (20 μM) significantly potentiated 4-12 Hz oscillatory activity as evidenced by significant increases in the parameters of power amplitude and power area but had no effect on large amplitude population spikes. These data indicate that pharmacological modulation of the M-current can influence excitability of nociceptive circuitry especially under conditions of central hyperexcitability, as may occur in chronic pain conditions. It is not clear whether these effects reflect a direct effect on interneurones localized to SG or indirectly via sensory afferent terminals. Nonetheless, these central actions should be taken into account alongside peripheral actions in terms of evaluating the potential therapeutic analgesic potency of novel M-current enhancers.