Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Na) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Na1.2, Na1.3, Na1.6, Na1.7, and Na1.8 with a β subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the β subunit on the effect of antidepressants on Na1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with β. The inhibitory effects were more potent for Na1.3, Na1.7, and Na1.8, which are distributed in dorsal root ganglia, than Na1.2 and Na1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Na1.7 with β was most potent with a half-maximal inhibitory concentration (IC) 4.6 μmol/L. IC for amitriptyline on Na1.3 coexpressed with β was lowered from 8.4 to 4.5 μmol/L by coexpression with β. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the β subunit appears important for inhibition of Na1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.

BACKGROUND: The transient receptor potential vanilloid subtype 3 (TRPV3) channel is activated by innocuous temperature and several chemical stimuli. It is proposed to be involved in pathological pain development and is therefore considered a potential target for treating pain. Local anesthetics have been used for patients with both acute and chronic pain. Although blockage of the voltage-gated sodium channel is the primary mechanism by which local anesthetics exert their effects, they cannot be explained by this mechanism alone, especially in pathologic states such as chronic pain. Indeed, the effects of local anesthetics on multiple targets involved in the pain pathway have been reported. It has also been suggested that modulating the function of transient receptor potential (TRP) channels (eg, TRPV1 and transient receptor potential ankyrin 1 [TRPA1]) is one of the mechanisms of action of local anesthetics. However, the effects of local anesthetics on TRPV3 have not been reported. METHODS: We expressed TRPV3 in Xenopus oocytes and investigated the effects of local anesthetics on 2-aminoethoxydiphenyl borate (2APB)–induced currents using 2-electrode voltage-clamp techniques. RESULTS: Clinically used local anesthetics inhibited the 2APB-activated currents from the TRPV3 channel in a concentration-dependent manner at pharmacologically relevant concentrations with half maximal inhibitory concentration (IC50) values of 2.5 (lidocaine), 1.4 (mepivacaine), 0.28 (ropivacaine), and 0.17 (bupivacaine) mmol/L, respectively. Conversely, these local anesthetics also directly induced currents at higher concentrations, although these currents were quite small compared to the 2APB-induced currents. We found that the inhibition of TRPV3 by lidocaine is noncompetitive and independent of intracellular signaling cascades. 2APB-induced TRPV3 currents were reduced by extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) but not by intracellular QX-314 nor benzocaine. Moreover, lidocaine showed a use-dependent block in TRPV3 inhibition. Finally, QX-314 appeared to slightly permeate the activated TRPV3 channel pore based on examination of oocytes coexpressing TRPV3 and a sodium channel. These results suggest that local anesthetics could inhibit TRPV3 channel function by extracellular interactions of their charged forms with the channel pore. CONCLUSIONS: Local anesthetics inhibited TRPV3 2APB-induced currents at pharmacologically relevant concentrations when TRPV3 was expressed in Xenopus oocytes. These effects seem to occur via an extracellular interaction between the charged form of the anesthetic with the TRPV3 channel pore. These results help to elucidate the mechanisms of action of local anesthetics.

The neurosteroid allopregnanolone has potent analgesic effects, and its potential use for neuropathic pain is supported by recent reports. However, the analgesic mechanisms are obscure. The voltage-gated sodium channels (Na) α subunit Na1.3 is thought to play an essential role in neuropathic pain. Here, we report the effects of allopregnanolone sulfate (APAS) on sodium currents (I) in Xenopus oocytes expressing Na1.3 with β or β subunits. APAS suppressed I of Na1.3 with β and β in a concentration-dependent manner (IC values; 75 and 26 μmol/L). These results suggest the possible importance of Na1.3 inhibition for the analgesic mechanisms of allopregnanolone.

Yetmiş iki yaşındaki bir erkek hastaya (boy: 160 cm, ağırlık: 53 kg) sol renal ve uterin septum rezeksiyonu uygulanması planlandı. Hasta 14 yıl öncesinde, sağ maksiller sinüste oluşan ve orbita tabanına yayılım gösteren yassı epitel hücreli karsinoma tedavisi için orbital ekzenterasyon ile birlikte sağ radikal maksillofasiyel cerrahi geçirmiş. Anestezist, maskenin hastanın yüzüne uygun olmasına rağmen, orbita çevresindeki yapışkan bant hareket ettiği için, indüksiyon boyunca maske ventilasyonunun uygulanmasında zorluk yaşadı. Acil olarak yapılan endotrakeal entübasyon, desatürasyon olmadan başarılı bir şekilde uygulandı. Postoperatif incelemede nazal kavite ile orbita arasındaki temasın ameliyattan 9 yıl önce çekilen bilgisayarlı tomogramlarda görülebildiği ortaya çıktı. Hasta yapışkan bant etrafındaki hava kaçağını hissedebiliyordu. Anestezistin lezyonu direkt olarak gözlemlemek için yapış-kan bandı çıkarması ve temasın maske ventilasyonunda zorluğa neden olabileceğini farketmesi gerekiyordu. Bilgisayarlı tomografi kullanarak havayollarının detaylı bir şekilde incelenmesi ve görüş-melerin dikkatli yapılmasıyla, havayolları daha iyi anlaşılabilir ve benzer olaylardan kaçınılabilir. Anahtar Kelimeler: Havayolu yönetimi, maksillofasiyel cerrahi, orbitaA 72-year-old male (height: 160 cm, weight: 53 kg) was scheduled to undergo left renal and male with ans uterine tract resection. The patient had previously undergone right radical maxillofacial surgery with orbital exenteration 14 years before the present operation to treat squamous cell carcinoma of the right maxillary sinus, with tumour invasion to the orbital floor. An anaesthesiologist encountered difficulty in performing mask ventilation during the induction of anaesthesia in the patient, despite a good mask fit on the face, because the adhesive tape around the orbit had moved. Urgent endotracheal intubation was successful without desaturation. A postoperative examination revealed that a communication between the nasal cavity and the orbit was visible on computed tomograms obtained nine years before the surgery. The patient felt the air leakage around the adhesive tape. The anaesthesiologist should have removed the adhesive tape to directly observe the lesion and should have realised that the communication might cause difficulty in mask ventilation. Careful examination of the airways using computed tomography and precise interviews may improve the understanding of patients' airways and may help avoid similar events.

This technique was feasible, and the procedure was performed safely. Our novel analgesia technique has potential use as a standard postoperative regimen in various laparoscopic surgeries. Additional prospective studies to compare it with other techniques are required.