What is the main mechanism of tramadol?

Tramadol is an analgesic that is used worldwide for pain, but its mechanisms of action have not been fully elucidated. The majority of studies to date have focused on activation of the µ-opioid receptor (µOR) and inhibition of monoamine reuptake as mechanisms of tramadol. Although it has been speculated that tramadol acts primarily through activation of the µOR, no evidence has revealed whether tramadol directly activates the µOR. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of ion channels and G protein-coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for tramadol. In particular, tramadol has been shown to affect GPCRs. Here, the effects of tramadol on GPCRs, monoamine transporters, and ion channels are presented with a discussion of recent research on the mechanisms of tramadol.

Kisspeptin-10 potentiates miniature excitatory postsynaptic currents in the rat supraoptic nucleus.

Kisspeptin is the natural ligand of the G protein-coupled receptor -54 and plays a major role in gonadotropin-releasing hormone secretion in the hypothalamus. Kisspeptin-10 is an endogenous derivative of kisspeptin and has 10 -amino acids. Previous studies have demonstrated that central administration of kisspeptin-10 stimulates the secretion of arginine vasopressin (AVP) in male rats. We examined the effects of kisspeptin-10 on- excitatory synaptic inputs to magnocellular neurosecretory cells (MNCs) including AVP neurons in the supraoptic nucleus (SON) by obtaining in vitro whole-cell patch-clamp recordings from slice preparations of the rat brain. The application of kisspeptin-10 (100 nM-1 µM) significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) in a dose-related manner without affecting the amplitude. The kisspeptin-10-induced potentiation of the mEPSCs was significantly attenuated by previous exposure to the kisspeptin receptor antagonist kisspeptin-234 (100 nM) and to the protein kinase C inhibitor bisindolylmaleimide I (20 nM). These results suggest that kisspeptin-10 participates in the regulation of synaptic inputs to the MNCs in the SON by interacting with the kisspeptin receptor.

High-frequency stimulation restored motor-evoked potentials to the baseline level in the upper extremities but not in the lower extremities under sevoflurane anesthesia in spine surgery.

BACKGROUND: Volatile anesthetics attenuate medium-frequency (250 to 500 Hz) pulse train transcranial electrical stimulation (TES) motor-evoked potentials (MEPs) better than propofol. High-frequency (1000 Hz) TES may restore hand MEP amplitude under volatile anesthesia, but its effect on leg MEPs critical for spine surgery monitoring is unknown. METHODS: The effects of sevoflurane and propofol and modulation of the stimulation frequencies on MEPs elicited by TES in the anterior tibial, abductor hallucis, and abductor pollicic brevis muscles were investigated in 31 patients undergoing spine surgery. MEPs elicited by transcranial magnetic stimulation were also obtained before the surgeries and compared with the TES MEPs. RESULTS: Sevoflurane attenuated the MEP amplitudes significantly. The MEP amplitudes increased with the TES frequency in the case of the arms, but not the legs, under sevoflurane anesthesia. The MEPs recorded under propofol anesthesia did not differ from those elicited by transcranial magnetic stimulation before the surgery (control). CONCLUSIONS: Sevoflurane is inadvisable for MEP monitoring in the legs during spine surgery as modulation of the TES frequency did not eliminate the suppressive effect of sevoflurane on the MEPs in the legs. Clinicians should be forewarned of the greater risk of unmonitorable MEPs, especially in the legs, under sevoflurane anesthesia.

Sevoflurane inhibits the µ-opioid receptor function expressed in Xenopus oocytes.

Sevoflurane is widely used for anesthesia, and is commonly used together with opioids in clinical practice. However, the effects of sevoflurane on µ-opioid receptor (µOR) functions is still unclear. In this study, the effects of sevoflurane on µOR functions were analyzed by using Xenopus oocytes expressing a µOR fused to chimeric Gα protein G(qi5) (µOR-G(qi5)). Sevoflurane by itself did not elicit any currents in oocytes expressing µOR-G(qi5), whereas sevoflurane inhibited the [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO)-induced Cl(-) currents at clinically used concentrations. Sevoflurane did not affect the Cl(-) currents induced by AlF(4)(-), which directly led to activation of G proteins. The inhibitory effects of sevoflurane on the DAMGO-induced currents were not observed in oocytes pretreated with the protein kinase C (PKC) inhibitor GF109203X. These findings suggest that sevoflurane would inhibit µOR function. Further, the mechanism of inhibition by sevoflurane would be mediated by PKC.

Effects of sevoflurane on voltage-gated sodium channel Na(v)1.8, Na(v)1.7, and Na(v)1.4 expressed in Xenopus oocytes.

Sevoflurane is widely used as a volatile anesthetic in clinical practice. However, its mechanism is still unclear. Recently, it has been reported that voltage-gated sodium channels have important roles in anesthetic mechanisms. Much attention has been paid to the effects of sevoflurane on voltage-dependent sodium channels. To elucidate this, we examined the effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 expressed in Xenopus oocytes. The effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 sodium channels were studied by an electrophysiology method using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. Sevoflurane at 1.0 mM inhibited the voltage-gated sodium channels Na(v)1.8, Na(v)1.4, and Na(v)1.7, but sevoflurane (0.5 mM) had little effect. This inhibitory effect of 1 mM sevoflurane was completely abolished by pretreatment with protein kinase C (PKC) inhibitor, bisindolylmaleimide I. Sevoflurane appears to have inhibitory effects on Na(v)1.8, Na(v)1.4, and Na(v) 1.7 by PKC pathways. However, these sodium channels might not be related to the clinical anesthetic effects of sevoflurane.

The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes.

Tramadol has been widely used as analgesic. O-Desmethyl tramadol (ODT) is one of the main metabolites of tramadol, having much greater analgesic potency than tramadol itself. Substance P receptors (SPR) are well known to modulate nociceptive transmission within the spinal cord. In this study, we investigated the effects of ODT on SPR expressed in Xenopus oocytes by examining SP-induced Ca(2+)-activated Cl(-) currents. ODT inhibited the SPR-induced Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ODT on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that the tramadol metabolite ODT inhibits the SPR functions, which may be independent of activation of PKC-mediated pathways.

[Screening of sleep apnea syndrome with Sleeprecorder SD-101].

Polysomnography (PSG) has been the gold standard for the diagnosis of sleep apnea syndrome (SAS). However, PSG is not generally available since it is technically demanding, and cost and labour are necessary. Currently, there is growing demand for its diagnosis. Thus, simplified portable equipments have been increasingly utilized. Sleeprecorder SD-101 (Suzuken, Nagoya, Japan) is a pad-shaped and novel device for SAS analysis. A total of 162 sitting-sensor tips are 1.6 inch apart, embeded in the 55 x 22 inch pad, and capable of detecting load with precision of one gram. Sleeprecorder SD-101 placed beneath the chest can recognize respiratory pattern and record thoracic movement during sleep. SASLyzer (Suzuken, Nagoya, Japan), a software installed in a compatible PC, analyzes the data and indicates apnea-hypopnea index (AHI). We present a case of SAS in a 40-year-old man (181 cm, 98 kg) with peritonsillitis. We used Sleeprecorder SD-101 since he complained of severe snoring and excessive daytime sleepiness. He had severe SAS with AHI 50.7. Subsequently, conventional PSG also indicated AHI 77. In the present case with severe SAS, these two methods showed equivalent severity. Sleeprecorder SD-101 could be a useful device for screening of SAS patients.

[Anesthesia in a patient with alkaptonuric ochronosis for total hip arthroplasty].

Alkaptonuric ochronosis, caused by a deficiency of homogentisate 1,2-dioxygenase, is a rare, autosomal recessive, metabolic disorder. Accumulation of homogentisate acid (HGA) at the connective tissue destructs the spine and large joints, and cardiac valvular disease is prominent. In this report, we describe a case of alkaptonuric ochronosis for anesthetic management. A 75-year-old female patient with the disease was scheduled for a total-hip arthroplasty. We avoided applying general anesthesia for her valvular regurgitations. Spinal anesthesia was achieved successfully, and resulted in a hypesthesia level at T12. Although a epidural catheter was indwelled with no leak of cerebrospinal fluid, an accidental dural puncture appeared later during the surgery, suggesting a subdural catheterization. She had an uneventful perioperative course without any symptoms. In the patient of alkaptonuric ochronosis, the dura and arachnoid membrane could be damaged made vulnerable by HGA. In addition, since the clinical findings resemble ankylosing spondylitis, degenerative changes such as a narrowing of the disk space and spine fusion would make the regional technique unsuccessful. In term of anesthesia, alkaptonuric ochronosis requires ingenuity since there are a number of factors associated with prevention of untoward complications. Each case is to be evaluated individually and managed carefully.

[Effects of colforsin daropate hydrochloride on myocardium, smooth muscle and renal function].

In the failing heart, numerous changes occur in cardiac adrenergic receptors (ARs) and intracellular signal transduction pathways. The most striking of these alterations appears at beta1 ARs, and the desensitization is the most prominent. Since malfunctions of beta1 ARs prevent intracellular signal transduction, the desensitization plays an important role in the onset and progression of the heart failure. Currently, several lines of evidence show the efficacy of inotropic agents, such as adenylate cyclase activator, that depend not on the ARs. Thus, it is essential to understand the pathway for the etiologic/pathologic evaluation for appropriate usage of these drugs for an adequate period. A novel water-soluble forskolin derivative, colforsin daropate hydrochloride (CDH) is a positive inotropic agent for treatment of the heart failure, especially in the severe stage with the beta1 AR desensitization. CDH potentiates cAMP activity via its direct action on adenylate cyclase, resulting in cardiotonic action. On the other hand, CDH relaxes vascular smooth muscle, while it antagonizes antidiuretic effects of angiotensin II and noradrenaline, involved in renal protection. In addition, CDH attenuates the mesangial cell proliferation and the inflammatory reaction, related with antiproliferative property of adrenomedullin and ketamine. To gain insights into the CDH action, we should take into account that intracellular signal transduction pathways in myocardium, smooth muscle and mesangial cell are controlled in a distinct manner.

The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes.

PURPOSE: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT(2C)R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT(2C)R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT(2C)R expressed in Xenopus oocytes. METHODS: We examined the effect of O-desmethyl tramadol on 5-HT(2C)R using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [(3)H]5-HT by 5-HT(2C)R. RESULTS: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca(2+)-activated Cl(-) currents in oocytes that expressed 5-HT(2C)R. The inhibitory effect of O-desmethyl tramadol on 5-HT(2C)R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [(3)H]5-HT by 5-HT(2C)R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [(3)H]5-HT by 5-HT(2C)R without changing maximum binding, which indicated competitive inhibition. CONCLUSION: These results suggest that O-desmethyl tramadol inhibits 5-HT(2C)R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol.

Effects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytes.

Alcohols, inhaled anesthetics, and some injectable anesthetics inhibit the function of N-methyl-d-aspartate (NMDA) receptors, but the mechanisms responsible for this inhibition are not fully understood. Recently, it was shown that ethanol inhibition of NMDA receptors was reduced by mutation of residues in the transmembrane (TM) segment 3 of the NR1 subunit (F639A) or in TM4 of the NR2A subunit (A825W), suggesting putative ethanol binding sites. We hypothesized that the actions of other anesthetics might also require these amino acids and evaluated the effects of anesthetics on the NMDA receptors expressed in Xenopus oocytes with two-electrode voltage-clamp recording. Effects of hexanol, octanol, isoflurane, halothane, chloroform, cyclopropane, 1-chloro-1,2,2-trifluorocyclobutane, and xenon were reduced or eliminated in the mutant NMDA receptors, whereas the inhibitory effects of nitrous oxide, ketamine, and benzene were not affected by these mutations. Rapid applications of glutamate and glycine by a T-tube device provided activation time constants, which suggested different properties of ketamine and isoflurane inhibition. Thus, amino acids in TM3 and TM4 are important for the actions of many anesthetics, but nitrous oxide, benzene, and ketamine seem to have distinct mechanisms for inhibition of the NMDA receptors.

[Complications related to anesthesia in the University of Occupational and Environmental Health Hospital].

BACKGROUND: Complications related to anesthesia remain a problem. We studied the incidence of complications during anesthesia in 2688 patients who had undergone anesthesia in the University of Occupational and Environmental Health Hospital. METHODS: We checked the anesthesia records retrospectively and analyzed the collected data for the incidence of complications during anesthesia. RESULTS: The total incidence of complications during anesthesia was 8.7%:5.5% related to circulation and 1.9% to respiration. CONCLUSIONS: Complications related to anesthesia should be prevented as much as possible through anesthesiologists' efforts in protocol development and skilled assistance.

The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors.

O-desmethyl tramadol is one of the main metabolites of tramadol. It has been widely used clinically and has analgesic activity. Muscarinic receptors are involved in neuronal functions in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets for analgesic drugs in the central nervous system. We have reported that tramadol inhibits the function of type-1 muscarinic (M(1)) receptors and type-3 muscarinic (M(3)) receptors, suggesting that muscarinic receptors are sites of action of tramadol. However, the effects of O-desmethyl tramadol on muscarinic receptor functions have not been studied in detail. In this study, we investigated the effects of O-desmethyl tramadol on M(1) and M(3) receptors, using the Xenopus oocyte expression system. O-desmethyl tramadol (0.1-100 microM) inhibited acetylcholine (ACh)-induced currents in oocytes expressing the M(1) receptors (half-maximal inhibitory concentration [IC(50)] = 2 +/- 0.6 microM), whereas it did not suppress ACh-induced currents in oocytes expressing the M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the ACh-induced current, it had little effect on the inhibition of ACh-induced currents by O-desmethyl tramadol in oocytes expressing M(1) receptors. The inhibitory effect of O-desmethyl tramadol on M(1) receptor was overcome when the concentration of ACh was increased (K(D) with O-desmethyl tramadol = 0.3 microM). O-desmethyl tramadol inhibited the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to the oocytes expressed M(1) receptors (IC(50) = 10.1 +/- 0.1 microM), whereas it did not suppress the specific binding of [(3)H]QNB to the oocytes expressed M(3) receptors. Based on these results, O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. This study demonstrates the molecular action of O-desmethyl tramadol on the receptors and may help to explain its neural function.

The effects of the neurosteroids: pregnenolone, progesterone and dehydroepiandrosterone on muscarinic receptor-induced responses in Xenopus oocytes expressing M1 and M3 receptors.

The neurosteroids pregnenolone, progesterone, and dehydroepiandrosterone (DHEA) occur naturally in the nervous system. They act on neural tissues, participate in neuronal signaling, and are reported to alter neuronal excitability via nongenomic mechanisms. Muscarinic receptors have important roles in neuronal functions in the brain and autonomic nervous system. In this study, we investigated the effects of pregnenolone, progesterone, and DHEA on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Pregnenolone and progesterone inhibited the acetylcholine (ACh)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. The half-maximal inhibitory concentrations (IC(50)) for pregnenolone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 11.4 and 6.0 microM respectively; the IC(50) values for progesterone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 2.5 and 3.0 microM respectively. The selective protein kinase C (PKC) inhibitor GF109203X had little effect on the pregnenolone or progesterone inhibition of the ACh-induced currents in Xenopus oocytes expressing M(1) or M(3) receptors. The inhibitory effects of pregnenolone and progesterone were overcome at higher concentrations of ACh. Pregnenolone and progesterone inhibited the [(3)H]quinuclidinyl benzilate (QNB) binding to M(1) and M(3) receptor expressed in Xenopus oocytes, and Scatchard plot analysis of [(3)H]QNB binding revealed that pregnenolone and progesterone altered the K(d) value and the B(max), indicating noncompetitive inhibition. In conclusion, pregnenolone and progesterone inhibited M(1) and M(3) receptor functions noncompetitively by the mechanism independent of PKC and by interfering with ACh binding to the receptors.

[Complications related to anesthesia method in the University of Occupational and Environmental Health Hospital].

BACKGROUND: Complications related to anesthesia remain a problem. We studied the incidence of complications during anesthesia in 2758 patients who had undergone anesthesia in the University of Occupational and Environmental Health Hospital. METHODS: We checked the anesthesia records retrospectively and analyzed the collected data for the incidence of complications during anesthesia. RESULTS: The total incidence of complications during anesthesia was 12.2%. The incidences of complication are estimated to be 13.4% in inhalation anesthesia, 11.9% in inhalation anesthesia plus epidural, spinal or conduction block, 8.9% in CSEA, zero % in epidural anesthesia and 7.5% in spinal anesthesia. CONCLUSIONS: The incidence of complications in inhalation anesthesia was almost as same as that in inhalation anesthesia plus epidural, spinal or conduction block. More study should be necessary to prevent complications related to anesthesia.

[The management of extirpation of chronic expanding hematoma after thoracoplasty in the chest].

A 71-year-old man was scheduled for an extirpation of chronic expanding hematoma (CEH) of his right thorax. He had a history of right thoracoplasty for tuberculosis 37 years previously. He complained of dyspnea that had deteriorated over three months. His inflammatory responses including general fatigue and fever due to chronic empyema remained to be resolved. The chest computed tomography revealed that the CEH remarkably compressed the trachea and the heart resulting in the cause of left mediastinal deviation. General anesthesia was induced with fentanyl and propofol, and maintained with sevoflurane. During general anesthesia, mean central venous pressure (CVP) via the right femoral vein and arterial blood pressure (ABP) via the left radial artery were monitored. Bilateral peripheral vein catheters with 16 G could effectively provide huge amount of transfusion. Although his blood loss was 10,000 ml because of superior vena caval rupture and oozing from pleura, prompt and adequate management of hemodynamics could be maintained using CVP and ABP monitoring. The CEH is known as a specific type of chronic empyema and its extraction would require ingenuity since there are number of factors associated with diagnosis, indication and prevention. Each case is to be evaluated individually and managed carefully.

[The airway management using laryngeal mask airway and tracheal fiberscopy in a pediatric patient with tracheal stenosis after tracheostomy].

A 9-year-old boy was scheduled for excision of tracheal granuloma which had developed at the tip of a tracheostomy tube. Instead of a tracheostomy tube, a 4 mm ID tracheal tube was inserted via the tracheostomy beyond the tracheal constriction because of rapid development of respiratory failure. General anesthesia was induced and maintained with sevoflurane and oxygen via the tube, and a size 2.5 laryngeal mask airway (LMA) was inserted without muscle relaxant. Spontaneous respiration remained. Under monitoring by fiberoptic tracheoscopy via the LMA, the tracheal tube was extubated carefully. An 8 Fr. suction tube was indwelled via the tracheostomy beyond the stenosis for oxygen supply. After sealing the tracheostomy, he could breath spontaneously through the LMA. During the excision of tracheal granuloma by holmium:YAG laser, fiberoptic observation was continued via the LMA, and the procedure was performed without any complication. We conclude that the tracheal stenosis can be managed using the LMA, continuous fiberoptic monitoring and additional option of keeping spontaneous ventilation.

Gargling with povidone-iodine reduces the transport of bacteria during oral intubation.

PURPOSE: Nosocomial pneumonia remains a common complication in patients undergoing endotracheal intubation. This study examined the transport of bacteria into the trachea during endotracheal intubation, and evaluated the effects of gargling with povidone-iodine on bacterial contamination of the tip of the intubation tube. METHODS: In the gargling group, patients gargled with 25 mL of povidone-iodine (2.5 mg.mL(-1)). In the control group, patients gargled with 25 mL of tap water. Before tracheal intubation, microorganisms were obtained from the posterior wall of the patient's pharynx using sterile cotton swabs. After anesthesia, all patients were extubated and bacteria contaminating the tip of the tracheal tube were sampled and cultured. RESULTS: Before orotracheal intubation, all 19 patients who gargled with tap water (control group) had bacterial colonization on the posterior walls of the pharynx. This group included five patients who had methicillin-resistant staphylococcus aureus (MRSA) in their nasal cavity preoperatively and MRSA was also detected in the pharynx of four patients. Bacterial colonization was observed in all 19 patients who gargled with povidone-iodine (gargling group) and four patients carried MRSA in their nasal cavity, although no MRSA was detected in the pharynx. In the control group, all the patients had bacterial colonization at the tip of the tube after extubation. Additionally, MRSA was detected in two of the four patients. In the gargling group, povidone-iodine eradicated general bacteria and MRSA colonies in the pharynx before intubation and at the tip of the tube after extubation. CONCLUSION: Gargling with povidone-iodine before oral intubation reduces the transport of bacteria into the trachea.