Effect of nortriptyline on inhibitory synaptic transmission within the substantia gelatinosa of the trigeminal subnucleus caudalis in mice.

Abstract

Nortriptyline, a tricyclic antidepressant widely used for the treatment of neuropathic pain, produces antinociceptive effects that cannot be fully accounted for by monoamine reuptake inhibition alone. Increasing evidence indicates that tricyclic antidepressants directly influence neuronal excitability and synaptic transmission within central nociceptive pathways; their actions on inhibitory neurotransmission in the trigeminal system remain incompletely characterized. In the present study, we investigated the effects of nortriptyline on inhibitory synaptic transmission in substantia gelatinosa neurons of the trigeminal subnucleus caudalis using whole-cell patch-clamp recordings in mouse brainstem slices. Nortriptyline produced a concentration-dependent increase in the frequency of spontaneous inhibitory postsynaptic currents without altering event amplitude and in an action potential-independent manner, consistent with a presynaptic mechanism. This facilitation reflected enhanced release of both GABA and glycine from presynaptic terminals. Importantly, the nortriptyline-induced enhancement of inhibitory synaptic activity persisted under Ca²⁺-free extracellular conditions, indicating that extracellular Ca²⁺ influx is not required. Collectively, these findings demonstrate that nortriptyline enhances inhibitory synaptic transmission in trigeminal substantia gelatinosa neurons primarily through presynaptic mechanisms, likely involving intracellular Ca²⁺ mobilization, and provide a cellular framework for its modulatory effects on orofacial nociceptive processing.