title: Effect of amitriptyline on glycinergic transmission in rat medullary dorsal horn neurons.
abstract: 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 Cd(2+), a general voltage-dependent Ca(2+) 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 Ca(2+). In contrast, the depletion of intracellular Ca(2+) 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 Ca(2+) concentration, which might be mediated by the Ca(2+) release from the Ca(2+) stores rather than the Ca(2+) 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.
authors.affiliation: Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea.
authors.forename: Jin-Hwa
authors.initials: JH
authors.lastname: Cho
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Choi
authors.forename: Maan-Gee
authors.initials: MG
authors.lastname: Lee
authors.forename: Il-Sung
authors.initials: IS
authors.lastname: Jang
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D005998:Glycine / Q000502:physiology*; D009924:Organ Culture Techniques; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014275:Trigeminal Caudal Nucleus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D000639:Amitriptyline; D005998:Glycine