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.

A tracheobronchial stent insertion was scheduled under general anesthesia in a 67-year-old man with a gastric tube-bronchial fistula after esophagectomy for cancer. Because the duration of apnea was expected to be long, we decided to use percutaneous cardiopulmonary support (PCPS) for gas exchange. The catheter insertion for PCPS was done under spinal anesthesia to eliminate pain during the procedure. Total intravenous anesthesia was performed after PCPS started, and the patient was intubated orally. When the Y-stent was inserted through a rigid bronchoscope, the patient had to be extubated. After extubation, oxygen saturation in his right hand dropped temporarily, whereas that in his left hand remained at 100%. This discrepancy occurred because arterial blood that was not fully oxygenated circulated in his right limb due to cardiac output rather than PCPS. We could minimize this desaturation in the right limb by ventilating the right lung through intubation into the right main trachea. We were able to manage this patient without critical accidents through detailed planning and special attention under PCPS.

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.

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