Effect of amitriptyline on glycinergic transmission in rat medullary dorsal horn neurons

Amitriptyline, a representative tricyclic antidepressant, has been widely used for the treatment of neuropathic pain, such as post-herpetic and trigeminal neuralgia. In the present study, we investigated the effect of amitriptyline on glycinergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in acutely isolated medullary dorsal horn neurons by use of a conventional whole-cell patch-clamp technique. Amitriptyline (30 μM) significantly increased mIPSC frequency without affecting the current amplitude, suggesting that amitriptyline acts presynaptically to increase the probability of glycine release. Amitriptyline also directly inhibited the glycine receptor-mediated Cl− currents induced by lower concentrations of glycine. The amitriptyline-induced increase in mIPSC frequency was not affected either in the Na+-free external solutions or in the presence of Cd2+, a general voltage-dependent Ca2+ channel blocker, indicating that amitriptyline is unlikely to elicit a presynaptic depolarization. In addition, amitriptyline still increased mIPSC frequency even in the absence of extracellular Ca2+. In contrast, the depletion of intracellular Ca2+ stores with thapsigargin significantly reduced the extent of amitriptyline-induced increase in mIPSC frequency. These data suggest that amitriptyline increases spontaneous glycine release onto acutely isolated medullary dorsal neurons by increasing the intraterminal Ca2+ concentration, which might be mediated by the Ca2+ release from the Ca2+ stores rather than the Ca2+ influx from the extracellular space. The amitriptyline-induced modulation of glycinergic transmission could have a broad impact on the excitability of medullary dorsal neurons, and this mechanism would contribute, at least in part, to the anti-allodynic action of amitriptyline.

► Amitriptyline has been widely used for the treatment of neuropathic pain.
► Amitriptyline facilitates spontaneous glycine release onto dorsal horn neurons.
► Amitriptyline increases intraterminal calcium concentration.