Regulation of excitability in tonic firing substantia gelatinosa neurons of the spinal cord by small-conductance Ca2+-activated K+ channels

•The excitability of tonic-firing SG neurons can be modulated by SK channels.•The two-way modulation of synapses by SK channels can be mimicked by high or low Ca2+ solutions.•The excitability increases of SK channels are mediated by Ca2+ influx.•Apamin-sensitive and -insensitive Ca2+-activated potassium channels modulate excitability by different pathways.•SK channels in the dorsal horn are potential targets for novel therapeutic analgesics.

The excitability of substantia gelatinosa (SG) neurons in the spinal dorsal horn determines the processing of nociceptive information from the periphery to the central nervous system. Small conductance Ca2+-activated K+ (SK) channels on neurons supply strong negative feedback control on neuronal excitability by affecting afterhyperpolarization (AHP). However, the role of SK channels in regulating tonic-firing SG neuron excitability remains elusive. In the present study, whole-cell recordings were conducted in SG neurons from acute spinal cord slices of adult rats. The SK channel opener 1-ethyl-2-benzimidazolinone (1-EBIO) attenuated spike discharges and increased AHP amplitudes; this effect was mimicked by a high Ca2+ external solution. Systemic administration of 1-EBIO attenuated the thermal-induced nociception behavior. Conversely, the inhibition of SK channels with apamin, a specific SK channel inhibitor, increased neuronal excitability and decreased the AHP amplitudes; this effect was mimicked by a Ca2+-free external solution. Apamin increased excitatory synaptic transmission by increasing the amplitudes of evoked excitatory postsynaptic potentials (eEPSPs). This facilitation depended on N-methyl-d-aspartate (NMDA) receptors, extracellular Mg2+ and intracellular Ca2+. Voltage-gated Ca2+ channels (VGCCs) were also involved in the apamin-induced effects. Strikingly, 1-EBIO action on decreasing excitability persisted in the presence of apamin, indicating that 1-EBIO manipulates SK channels via a pathway rather than via apamin-sensitive SK channels. The data reveal a previously uncharacterized mechanism for manipulating SG neuronal excitability by Ca2+ conductances via both apamin-sensitive and apamin-insensitive pathways. Because SG neurons in the dorsal horn are involved in regulating nociception, manipulating neuronal excitability via SK channels indicates a potential therapeutic target.