Nefopam downregulates autophagy and c-Jun N-terminal kinase activity in the regulation of neuropathic pain development following spinal nerve ligation.

BACKGROUND: Neurodegeneration is associated with changes in basal cellular function due to the dysregulation of autophagy. A recent study introduced the involvement of autophagy during spinal nerve ligation (SNL). Nefopam has shown potential for reducing neuropathic pain, but the underlying mechanisms are unknown. Here, we investigated the effects of nefopam on neuropathic pain development following SNL, focusing on the involvement of autophagy. METHODS: The functional role of nefopam in capsaicin-induced autophagy was assessed by human glioblastoma M059 K cells. The neuropathic pain model was used to determine whether the effect of nefopam on pain control was mediated through autophagy control. Neuropathic pain was induced by L5 and L6 SNL in male rats randomized into three groups: Group S (sham-operated), Group C (received normal saline), and Group E (received nefopam). A behavioral test using a von Frey was examined. Expression changes of autophagy in response to nefopam was analyzed in spinal cord tissues (L4-L6) by immunoblotting and immunohistochemistry. RESULTS: The paw withdrawal threshold examined on days 3, 5, 7, and 14 post-SNL was significantly higher in Group E than in Group C. SNL increased the levels of microtubule-associated protein 1 light chain 3B (LC3B-1), with concomitant reduction of sequestosome 1 (SQTSM1/p62), compared with Group S, indicating that SNL induced autophagy. These effects were reversed by nefopam injection, and the results were confirmed by immunohistochemistry for LC3-I/II. Furthermore, SNL-mediated JNK activation was markedly decreased following nefopam injection. Hematoxylin and eosin staining on Day 14 post-SNL revealed that SNL caused lymphocyte infiltration and oligodendrocyte localization in the substantia gelatinosa of the dorsal gray horn, which were reduced by nefopam injection. CONCLUSION: Collectively, the mode of action of nefopam on neuropathic pain appears to be associated with downregulation of phospho-JNK and autophagy, as well as modulation of the immune response.

Effects of lidocaine, ketamine, and remifentanil on withdrawal response of rocuronium.

BACKGROUND: Rocuronium has been well known to produce withdrawal response in 50-80% patients when administered intravenously. Several drugs are administered prior injection of rocuronium to prevent the withdrawal response. We compared the preventive effect of lidocaine, ketamine, and remifentanil on the withdrawal response of rocuronium. METHODS: A total of 120 patients undergoing various elective surgeries were enrolled. Patients were allocated into 4 groups according to the pretreatment drugs (Group N, normal saline; Groups L, lidocaine 40 mg; Group K, ketamine 0.5 mg/kg; Group R, remifentanil 1 µg/kg). Patients received drugs prepared by dilution to 3 ml volume before injection of rocuronium. Withdrawal responses after injection of rocuronium were graded on a 4-point scale. Hemodynamic changes were observed before and after administration of pretreatment drugs and after endotracheal intubation. RESULTS: Incidence of withdrawal response was significantly lower in group L (20%), group K (30%), and group R (0%), than group N (87%). Severe withdrawal response was observed in 5 of the 30 patients (17%) in group L, and in 9 of the 30 patients (30%) in group K. There was no severe withdrawal response in group R. Mean blood pressure and heart rate were significantly decreased in group R compared to other groups. CONCLUSIONS: It seems that remifentanil (1 µg/kg intravenously) was the strongest and most effective in prevention of withdrawal response after rocuronium injection among the 3 drugs.

Effects of a preemptive alveolar recruitment strategy on arterial oxygenation during one-lung ventilation with different tidal volumes in patients with normal pulmonary function test.

BACKGROUND: Hypoxemia during one-lung ventilation (OLV) remains a major concern. The present study compared the effect of alveolar recruitment strategy (ARS) on arterial oxygenation during OLV at varying tidal volumes (Vt) with or without positive end-expiratory pressure (PEEP). METHODS: In total, 120 patients undergoing wedge resection by video assisted thoracostomy were randomized into four groups comprising 30 patients each: those administered a 10 ml/kg tidal volume with or without preemptive ARS (Group H and Group H-ARS, respectively) and those administered a 6 ml/kg tidal volume and a 8 cmH2O PEEP with or without preemptive ARS (Group L and Group L-ARS, respectively). ARS was performed using pressure-controlled ventilation with a 40 cmH2O plateau airway pressure and a 15 cmH2O PEEP for at least 10 breaths until OLV began. RESULTS: Preemptive ARS significantly improved the PaO2/FiO2 ratio compared to the groups that did not receive ARS (P < 0.05). The H-ARS group showed a highest PaO2/FiO2 ratio during OLV, the L-ARS and H groups showed similarly improved arterial oxygenation, which was significantly higher than in group L (P < 0.05). The plateau airway pressure in group H-ARS was significantly higher than in group L-ARS (P < 0.05). CONCLUSIONS: Preemptive ARS can improve arterial oxygenation during OLV. Furthermore, a 6 ml/kg tidal volume combined with 8 cmH2O PEEP after preemptive ARS may reduce the risk of pulmonary injury caused by high tidal volume during one-lung ventilation in patients with normal pulmonary function.

Effect on thermoregulatory responses in patients undergoing a tympanoplasty in accordance to the anesthetic techniques during PEEP: a comparison between inhalation anesthesia with desflurane and TIVA.

BACKGROUND: It has been known that positive end-expiratory pressure (PEEP) increases the vasoconstriction threshold by baroreceptor unloading. We compared the effect on the thermoregulatory responses according to anesthetic techniques between an inhalation anesthesia with desflurane and a total intravenous anesthesia (TIVA) with propofol and reminfentanil when PEEP was applied in patients undergoing tympanoplasty. METHODS: Forty-six patients with a scheduled tympanoplasty were enrolled and the patients were divided in two study groups. Desflurane was used as an inhalation anesthetic in group 1 (n = 22), while TIVA with propofol and remifentanil was used in group 2 (n = 24). PEEP was applied by 5 cmH2O in both groups and an ambient temperature was maintained at 22-24℃ during surgery. The core temperature and the difference of skin temperature between forearm and fingertip were monitored for about 180 minutes before and after the induction of general anesthesia. RESULTS: The final core temperature was significantly higher in group 2 (35.4 ± 0.7℃) than in group 1 (34.9 ± 0.5℃). Peripheral thermoregulatory vasoconstriction was found in 5 subjects (23%) in group 1 and in 21 subjects (88%) in group 2. The time taken for reaching the thermoregulatory vasoconstriction threshold was 151.4 ± 19.7 minutes in group 1 and 88.9 ± 14.4 minutes in group 2. CONCLUSIONS: When PEEP will be applied, anesthesia with TIVA may have more advantages in core temperature preservation than an inhalation anesthesia with desflurane.

Depressor action and vasorelaxation of methylene chloride fraction extracted from Rubus coreanum.

INTRODUCTION: The present study was designed to examine whether methylene chloride (CH2Cl2) fraction extracted from Rubus coreanum affects the contractility of the isolated thoracic aortic strips and blood pressure of normotensive rats. METHODS: One of the common carotid arteries or of the femoral arteries was catheterized with a polyethylene tubing. The tubing was connected to a pressure transducer, and pulse of the mean arterial blood pressure was recorded on a biological polygraph continuously. RESULTS: The CH2Cl2 fraction (range, 200 to 800 µg/mL) significantly depressed both phenylephrine (PE, 10 µM)- and high K(+) (56 mM)-induced contractile responses of the isolated thoracic aortic strips in a concentration-dependent fashion. In the simultaneous presence of N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) (an inhibitor of nitric oxide [NO] synthase, 300 µM) and the CH2Cl2 fraction (400 µg/mL), both PE- and high K(+)-induced contractile responses were recovered to the significant level of the corresponding control response in comparison with inhibition of CH2Cl2 fraction treatment alone. Moreover, in the simultaneous presence of the CH2Cl2 fraction after pretreatment with 0.4% CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propane sulfonate), both PE- and high K(+)-induced contractile responses were recovered to the significant level of the corresponding control response compared to the inhibitory response of CH2Cl2 fraction treatment alone. Also, in anesthetized rats, the CH2Cl2 fraction (range, 0.3 to 3.0 mg/kg) injected into a femoral vein dose-dependently produced depressor responses. This hypotensive action of the CH2Cl2 fraction was greatly inhibited after treatment with phentolamine (1 mg/kg), chlorisondamine (1 mg/kg), L-NAME (3 mg/kg/30 min), or sodium nitroprusside (30 µg/kg/30 min). Intravenous infusion of the CH2Cl2 fraction (range, 1.0 to 10.0 mg/kg/30 min) markedly inhibited norepinephrine-induced pressor responses. DISCUSSION: Taken together, these results demonstrate that the CH2Cl2 fraction causes vascular relaxation in the isolated rat thoracic aortic strips as well as hypotensive action in anesthetized rats. These vasorelaxation and hypotension of the CH2Cl2 fraction seem to be mediated at least by the increased NO production through the activation of NO synthase of the vascular endothelium and the inhibitory adrenergic modulation.

The effect of low dose ketamine and priming of cisatracurium on the intubating condition and onset time of cisatracurium.

BACKGROUND: Both ketamine and priming may accelerate the onset time of neuromuscular blocking agents. We investigate the effect of low dose ketamine and cisatracurium priming on the intubating condition and onset time of cisatracurium. METHODS: After Institutional Review Board approval, 120 consecutive patients undergoing general anesthesia were randomly assigned to one of 4 groups. All patients were injected one of normal saline (group C), cisatracurium 0.01 mg/kg (group P), ketamine 0.5 mg/kg (group K) and combination of cisatracurium 0.01 mg/kg, and ketamine 0.5 mg/kg (group PK) diluted into a 5 ml solution, followed 3 minutes later by cisatracurium 0.15 mg/kg in group C and K, and 0.14 mg/kg cisatracurium in priming group. Onset time was recorded the electromyographical responses using single twitch and intubating conditions were evaluated at 60 seconds after cisatracurium administration. RESULTS: The mean onset time was most significantly accelerated in Group PK and was also significantly more accelerated in Group P and K compared with Group C (P < 0.008). It was 112.7 ± 13.2, 91.4 ± 17.9, 84.9 ± 12.7 and 76.4 ± 8.3 seconds in Group C, P, K, and PK, respectively. Intubating conditions were significantly improved in Group P, K and PK than Group C (P < 0.008). Especially, Group PK showed most significant improvement of intubating conditions. CONCLUSIONS: The combination of the low dose ketamine and cisatracurium priming accelerated the onset time and was improved the intubating conditions.

Polyphenols of Rubus coreanum Inhibit Catecholamine Secretion from the Perfused Adrenal Medulla of SHRs.

The present study was attempted to investigate whether polyphenolic compounds isolated from wine, which is brewed from Rubus coreanum Miquel (PCRC), may affect the release of catecholamines (CA) from the isolated perfused adrenal medulla of the spontaneously hypertensive rats (SHRs), and to establish its mechanism of action. PCRC (20~180 microg/ml) perfused into an adrenal vein for 90 min relatively dose-dependently inhibited the CA secretory responses to ACh (5.32 mM), high K(+) (56 mM), DMPP (100 microM) and McN-A-343 (100 microM). PCRC itself did not affect basal CA secretion (data not shown). Also, in the presence of PCRC (60 microg/ml), the CA secretory responses to veratridine (a selective Na(+) channel activator (10 microM), Bay-K-8644 (a L-type dihydropyridine Ca(2+) channel activator, 10 microM), and cyclopiazonic acid (a cytoplasmic Ca(2+) -ATPase inhibitor, 10 microM) were significantly reduced, respectively. In the simultaneous presence of PCRC (60 microg/ml) and L-NAME (an inhibitor of NO synthase, 30 microM), the inhibitory responses of PCRC on the CA secretion evoked by ACh, high K(+), DMPP, and Bay-K-8644 were considerably recovered to the extent of the corresponding control secretion compared with that of PCRC-treatment alone. The level of NO released from adrenal medulla after the treatment of PCRC (60 microg/ml) was greatly elevated compared with the corresponding basal level. Taken together, these results demonstrate that PCRC inhibits the CA secretion from the isolated perfused adrenal medulla of the SHRs evoked by stimulation of cholinergic receptors as well as by direct membrane-depolarization. It seems that this inhibitory effect of PCRC is mediated by blocking the influx of calcium and sodium into the adrenal medullary chromaffin cells of the SHRs as well as by inhibition of Ca(2+) release from the cytoplasmic calcium store at least partly through the increased NO production due to the activation of NO synthase.