JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ogata, J.
Right arrow Articles by Ueta, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ogata, J.
Right arrow Articles by Ueta, Y.
Related Collections
Right arrow Mechanisms
Right arrow Pain
Right arrow Pharmacology

Anesth Analg 2004;98:1401-1406
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000108963.77623.A4

PAIN MEDICINE

The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes

Junichi Ogata, MD*, Kouichiro Minami, MD PhD*, Yasuhito Uezono, MD PhD{dagger}, Takashi Okamoto, MD*, Munehiro Shiraishi, MD*, Akio Shigematsu, MD PhD*, and Yoichi Ueta, MD PhD{ddagger}

*Department of Anesthesiology, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan, the {dagger}Second Department of Pharmacology, Nagasaki University School of Medicine, Nagasaki, Japan, and the {ddagger}First Department of Physiology, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan

Address correspondence and reprint requests to Kouichiro Minami, MD, PhD, Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1–1, Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka 807–8555, Japan. Address email to kminami{at}med.uoeh-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT2CR) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomotion. In this study, we used a whole-cell voltage clamp to examine the effects of tramadol on 5-HT-induced Ca2+-activated Cl– currents mediated by 5-HT2CR expressed in Xenopus oocytes. Tramadol inhibited 5-HT-induced Cl– currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor, bisindolylmaleimide I (GF109203x), did not abolish the inhibitory effects of tramadol on the 5-HT2CR-mediated events. We also studied the effects of tramadol on [3H]5-HT binding to 5-HT2CR expressed in Xenopus oocytes, and found that it inhibited the specific binding of [3H]5-HT to 5-HT2CR. Scatchard analysis of [3H]5-HT binding revealed that tramadol altered the apparent dissociation constant for binding without changing maximal binding, indicating competitive inhibition. The results suggest that tramadol inhibits 5-HT2CR function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT2CR, rather than via activation of the PKC pathway.

IMPLICATIONS: We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT2CR) expressed in Xenopus oocytes. Tramadol inhibited 5-HT2CR function and the specific binding of [3H]5-HT to 5-HT2CR in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT2CR might involve the competitive displacement of 5-HT binding to the 5-HT2CR.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Tramadol [(1R, 2R) and (1S, 2S)-2-dimethylamino-methyl-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] has been used as an analgesic for several decades. However, its mechanism of antinociception is unclear (1). Studies have shown that tramadol inhibits the uptake of [3H]5-HT into purified synaptosomes from the rat frontal cortex (2), which suggested that the analgesic effect of tramadol is related to serotonin as one of the mechanisms that modulate nociceptive perception. Recently, we found that tramadol inhibits the function of cholinergic receptors, such as muscarinic M1 and M3 receptors (3–5). These findings implicate G-protein coupled receptors (GPCR) as a target of tramadol action.

Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes in the mammalian central and peripheral nervous systems (6). Seven 5-HT receptor families have been identified, and diverse responses are elicited via the activation of these receptor subtypes (7). The 5-HT type 2C receptor (5-HT2CR) is one of the major 5-HT receptor subtypes in the brain (8) and belongs to the GPCR family (9). Because the receptor is expressed in cortical and subcortical neurons, including hippocampal pyramidal neurons and neurons in thalamic sensory relay nuclei where nociceptive transmission is regulated (7), its message is widely distributed in the brain (9). 5-HT2CR is implicated in many important effects of 5-HT, including pain, feeding, and locomotion (8). Several reports have indicated that 5-HT2CR-deficient mice show abnormal control of feeding behavior, resulting in overweight mice (8) that are prone to spontaneous death from seizures (10).

We previously reported that volatile anesthetics like halothane inhibit 5-HT type 2A receptors expressed in Xenopus oocytes (11). Moreover, recent studies have shown that tramadol has analgesic properties that are mediated by serotonergic 5HT1 and 2/3 receptors (12,13). These implicate the effects of anesthetics on 5-HT2CR in one of the mechanisms modulating nociceptive perception. However, there is little information on the action of tramadol on 5-HT2C receptors.

The Xenopus oocyte expression system is a superior technique for studying a multiplicity of brain receptors with pharmacological properties that mimic those of native brain receptors (14). Stimulation of 5-HT2CR leads to G-protein-dependent activation of phospholipase C (PLC), producing myo-inositol-1, 4, 5-trisphosphate (IP3) and diacylglycerol (DG) (15). IP3 causes the release of Ca2+ from the endoplasmic reticulum, which in turn triggers the opening of Ca2+-activated Cl– channels (14). This system has been well characterized, and has proven useful for evaluating the effects of analgesics on GPCR (4,5,11,16). Therefore, we used this technique for this investigation.

This study examined the effects of tramadol on 5-HT-induced Ca2+-activated Cl– currents in Xenopus oocytes expressing 5-HT2CR. In addition, we investigated the mechanism of the effects of tramadol on 5-HT2CR function.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Adult female Xenopus laevis frogs were purchased from Seac Yoshitomi (Yoshitomi, Fukuoka, Japan), 5-HT was from Sigma (St. Louis, MO), tramadol hydrochloride was a kind gift from Nippon Shinyaku (Kyoto, Japan), bisindolylmaleimide I (GF109203x) was from Calbiochem (La Jolla, CA), and the Ultracomp E. coli Transformation Kit was from Invitrogen (San Diego, CA). A Qiagen Kit (Chatworth, CA) was used to purify plasmid cDNA. 5-HT2CR cDNA from rats was kindly provided by Dr. Henry Lester (Caltech, Pasadena, CA). The 5-HT2CR cDNA was linearized with XbaI, and rat 5-HT2CR cRNA was prepared using an mCAP mRNA Capping Kit, and transcribed with a T7 RNA Polymerase in vitro Transcription Kit (Stratagene, La Jolla, CA).

Xenopus oocytes were isolated and microinjected, as described by Minami et al. (11,17). Briefly, Xenopus oocytes were injected with 50 ng of cRNA encoding 5-HT2CR. The oocytes were placed in a 100-µL recording chamber and perfused with MBS (modified Barth’s saline) containing 88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO3, 10 mM HEPES, 0.82 mM MgSO4, 0.33 mM Ca(NO3)2, and 0.91 mM CaCl2, (pH 7.5) at a rate of 1.8 mL/min at room temperature. The recording and clamping electrodes (1–5 M{Omega}) were pulled from capillary tubing with a 1.2-mm outside diameter and filled with 3 M KCl. A Warner OC 725-B oocyte clamp (Hampden, CT) was used to voltage-clamp each oocyte at –70 mV. We analyzed the peak of the transient inward current component of the 5-HT2CR-induced currents because this component is dependent on 5-HT concentration and is quite reproducible, as described by Minami et al. (11). Tramadol was pre-applied for 2 min to allow complete equilibration in the bath. The solution of IV tramadol was freshly prepared immediately before use. The concentrations in the figures represent the bath concentrations.

To determine whether protein kinase C (PKC) activation plays a role in the modulatory effect of tramadol on 5-HT2CR-mediated events, oocytes were treated with the PKC inhibitor bisindolylmaleimide I (GF109203x) (200 nM) (18) in MBS for 240 min. 5-HT was applied at 60, 120, 180, and 240 min during the GF109203x treatment. As a control, 5-HT was similarly applied to oocytes that were not treated with GF109203X. We also investigated the effects of tramadol on 5-HT-induced Cl– currents in oocytes pretreated with GF109203x for 120 min.

The binding of [3H]5-HT to Xenopus oocytes was examined in the following manner. For groups expressing or not expressing 5-HT2CR, 3 Xenopus oocytes per tube were incubated for 60 min at 25°C with MBS (final volume 0.5 mL) containing [3H]5-HT (0.1–10 nM) in the presence or absence of tramadol. Three oocytes per tube were used for total binding and nonspecific binding at a tramadol concentration of 10–5M. After incubation, binding was terminated by rapidly washing the oocytes 4 times with 5 mL of ice-cold MBS buffer under vacuum through Whatman GF/C glass-fiber filters, and the oocytes were placed in counting vials containing scintillation cocktail. The radioactivity was counted in an Aloka LSC-3500E counter (Tokyo, Japan). Specific binding of [3H]5-HT was defined as the binding inhibited by 10–8M 5-HT.

Results are expressed as percentages of the control responses attributable to the variable 5-HT2CR expression in oocytes. The control responses were measured before and after applying each drug to take into account possible shifts in the control currents as recording proceeded. The "n" values refer to the number of oocytes studied. Each experiment was performed with oocytes from at least two different frogs. Statistical analyses were performed using either Student’s t-test or a one-way analysis of variance. Curve fitting and estimation of IC50 values for the concentration-response curves were performed using GraphPad Inplot Software (San Diego, CA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
With drugs such as anesthetics, the modulation of receptor function often depends on the degree of receptor activation (14). Therefore, it was necessary to determine the 5-HT concentration-response relationship under our experimental conditions before examining the effect of tramadol (Fig. 1). Nonlinear regression analysis of the curve yielded an EC50 for 5-HT of 26 nM, a Hill coefficient of 1.1, and the maximal current was observed at 10–5 M (Fig. 1). Based on the results in Figure 1, the effects of tramadol on 5-HT-induced currents were examined at a 5-HT concentration of 10–8M.



View larger version (12K):
[in this window]
[in a new window]
  		Figure 1. Concentration-response curve for 5-HT activation of Ca2+-activated Cl– current in Xenopus oocytes expressing 5-HT2CR. Oocytes expressing 5-HT2CR were voltage-clamped at –70 mV. 5-HT (10–10 to 10–5 M) was bath-applied to the oocytes for 20 s and the peak Ca2+-activated Cl– current was measured. Values are the mean of the percentage of the maximal response at 10–5 M ± SEM from 10 oocytes. In some cases, the error bars are smaller than the symbols. Nonlinear regression analysis of the curve yielded an EC50 for 5-HT of 26 nM, a Hill coefficient of 1.1, and the maximal current was at 10–5 M.

 
Compared with the Ca2+-activated Cl– currents induced by 10–8M 5-HT as a control, tramadol suppressed the Cl– currents (Fig. 2A). After 60 min, all the Cl– currents produced by 10–8M 5-HT recovered completely (Fig. 2A). However, using the Cl– currents treated with 10–8 M 5-HT as a control current, 10–7 and 10–6 M 5-HT compensated the inhibitory effects of 10–6 M tramadol, respectively (Fig. 3).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 2. Effects of tramadol on 5-HT-elicited Cl– currents in oocytes expressing 5-HT2CR. A, oocytes expressing 5-HT2CR were voltage-clamped at –70 mV, and a representative recording trace from a single oocyte is shown. Oocytes were treated () with tramadol (10–5M) for 2 min before and during 5-HT (10–8M) application ({downarrow}) for 20 s. Compared with the 5-HT (10–8M)-elicited Cl– current as a control, after a 60-min interval tramadol (10–5M) suppressed the Cl– current caused by 5-HT (10–8 M). After an additional 60 min, the Cl– current produced by 5-HT recovered completely. B, the concentration-response curve of the inhibition of 5-HT (10–8 M)-induced Cl– currents by tramadol (10–8 to 10–4M). The data are the mean of the percentage of the control current ± SEM from 10 oocytes at each tramadol concentration. Tramadol (10–6 to 10–4M) inhibited the Cl– currents in oocytes expressing 5-HT2CR.

 


View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. Tramadol inhibits the Cl– currents elicited by sub-maximal concentrations of 5-HT in oocytes expressing 5-HT2CR. A, oocytes expressing 5-HT2CR were voltage-clamped at –70 mV, and a representative recording trace from a single oocyte is shown. 5-HT (10–8M) was bath-applied to the oocyte for 20 s as a control ({downarrow}). Then, tramadol (10–5M) was given () for 2 min before and during 5-HT (10–8 to 10–6M) application ({downarrow}) for 20 s after a 60-min interval. B, the concentration-response curve for 5-HT (10–8 to 10–6M) activation of the Cl– current with tramadol (10–6M) treatment. The data are the mean of the percentage of the control current ± SEM from 10 oocytes at each 5-HT concentration. The inhibition of the Cl– current by tramadol (10–5M) was overcome by sub-maximal concentrations of 5-HT (10–7 and 10–6M) in oocytes expressing 5-HT2CR.

 
Several reports have shown that some anesthetics inhibit GPCR functions by modulating PKC pathways (11,16). Therefore, we also investigated whether the inhibitory effects of tramadol on 5-HT2CR-mediated events could be the result of modulation of PKC pathways. For this purpose, we used Xenopus oocytes pretreated with the specific PKC inhibitor GF109203x (200 nM), which has a Ki value for inhibiting PKC activity of 20 nM (18). Treatment with GF109203x alone produced a 5.2-fold enhancement in the initial Cl– currents induced by 10–8 M 5-HT (Fig. 4A and B). Tramadol also inhibited the 5-HT-induced currents in oocytes pretreated with GF109203X (Fig. 4C and D).



View larger version (25K):
[in this window]
[in a new window]
  		Figure 4. Effects of a specific protein kinase C (PKC) inhibitor, GF109203X, on 5-HT-elicited currents (A, B) and the inhibitory effects of tramadol on 5-HT-elicited currents (C, D) with GF109203x treatment. A, oocytes expressing 5-HT2CR were voltage-clamped at –70 mV, and a representative recording trace from a single oocyte is shown. After 5-HT (10–8M) was bath-applied to the oocyte for 20 s as a control (first bow), it was treated with GF109203x (200 nM) for 60 min (). Then, 5-HT (10–8M) was applied ({downarrow}) for a 60-min interval during the GF109203x (200 nM) treatment (). B, the effects of GF109203x on the 5-HT-elicited Cl– current in oocytes expressing 5-HT2CR. The data are the mean of the percent of the control current ± SEM from 8 oocytes for each time course. C, oocytes expressing 5-HT2CR were voltage-clamped at –70 mV, and a representative recording trace from a single oocyte is shown. Oocytes were pretreated with GF109203X (200 nM) for 120 min and during the subsequent investigations (). 5-HT (10–8M) was bath-applied to the oocyte for 20 s as a control ({downarrow}). After 60 min, tramadol (10–5M) was added for 2 min before () and during 5-HT (10–8M) application for 20 s ({downarrow}). Compared with the control, tramadol (10–5M) suppressed the Cl– current elicited by 5-HT (10–8M). After an additional 60 min, the Cl– current recovered completely. D, comparison of the inhibitory effect of tramadol (10–5M) on the 5-HT (10–8M)-induced Cl– current with GF109203x treatment. The data are the mean of the percentage of the control current ± SEM from four separate determinations. Compared with the control current, tramadol (10–5M) suppressed the Cl– current elicited by 5-HT (10–8M). After a 60-min interval, the Cl– current recovered completely. However, the action of GF109203X was not significant (P > 0.05, paired t-test).

 
We further examined the effects of tramadol on the binding of [3H]5-HT to 5-HT2CR. Specific binding of [3H]5-HT was saturable with increasing [3H]5-HT concentration (0.1–10 nM) (Fig. 5A). A Scatchard analysis showed a single population of binding sites, with an apparent dissociation constant (Kd) of 7 nM and maximal binding (Bmax) of 25.6 pmol/3 oocytes (Fig. 5B). The specific binding of [3H]5-HT was inhibited by 10–5 M tramadol and was not reversed by increasing the concentration of [3H]5-HT (Fig. 5A). From the Scatchard plot analysis, tramadol altered the Kd of [3H]5-HT binding (28 nM) without changing Bmax (26.0 pmol/3 oocytes) (Fig. 5B).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 5. Saturation and Scatchard analyses of [3H]5-HT binding to 5-HT2CR expressed in Xenopus oocytes. A, oocytes (3 oocytes/tube) expressing 5-HT2CR were incubated for 60 min at 25°C in the presence () or absence () of tramadol (10–5M) with increasing [3H]5-HT (10–10 to 10–8 M) concentrations. The data are the means ± SEM of four separate experiments. Tramadol (10–5M) inhibited the specific binding of [3H]5-HT and this was not reversed by increasing the [3H]5-HT concentration. B, Scatchard analysis of the specific binding of [3H]5-HT from Figure 4A. A Scatchard analysis of the specific binding of [3H]5-HT showed a single population of binding sites, with an apparent dissociation constant (Kd) of 7 nM and maximal binding (Bmax) of 25.6 pmol/3 oocytes. From the analysis, tramadol altered the Kd of [3H]5-HT binding (28 nM) without changing Bmax (26.0 pmol/3 oocytes).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we showed that tramadol inhibited the 5-HT2CR expressed in Xenopus oocytes. According to Lintz et al. (19), the concentration of tramadol in human serum reaches 612.7 ± 221 ng/mL (approximately 2 µM) after IV injection of 100 mg tramadol, which is the clinical dosage. In this study, 1 and 10 µM tramadol inhibited the 5-HT-induced Cl– currents to 79.16% ± 3.27% and 69.09% ± 5.11% of the control, respectively. These findings suggest that tramadol suppresses the function of 5-HT2CR at clinically relevant concentrations.

Next, we examined how tramadol inhibits 5-HT2CR function. There is considerable evidence that PKC plays an important role in regulating several types of GPCR. Ethanol and volatile anesthetics such as isoflurane are reported to suppress the function of muscarinic (17) and substance P (16) receptors via the modulation of PKC pathways. Alcohols and volatile anesthetics also inhibit 5-HT2AR, and these actions are dependent on PKC (11). We showed that the selective PKC inhibitor GF109203x enhanced 5-HT2CR function, indicating that 5-HT2CR function can be modulated by changing the PKC activity. However, GF109203x did not abolish the inhibitory effects of tramadol on 5-HT2CR function, suggesting that tramadol inhibits 5-HT2CR function without modulating PKC pathways. Moreover, we previously reported that tramadol does not interfere with the pathway after G-protein-coupled signal transduction, such as PLC activation, intracellular Ca2+ release, and Ca2+-activated Cl– currents (4). It has also been reported that tramadol has no effects on the function of another Gq-coupled substance P receptor, although they share the same intracellular signaling pathways as 5-HT2CR (unpublished data). Moreover, tramadol did not inhibit the Cl– currents induced by large 5-HT concentration, suggesting that tramadol competitively inhibits 5-HT2CR function. From this and previous evidence, it is likely that the inhibitory effect of tramadol on the 5HT-induced Cl– current is attributable to the direct inhibition of 5HT2CR.

To confirm this hypothesis, we examined the effects of tramadol on [3H]5-HT binding to 5-HT2CR expressed in Xenopus oocytes. Scatchard plot analysis of [3H]5-HT binding revealed that tramadol altered the Kd without changing the Bmax, indicating competitive inhibition. These findings suggest that tramadol inhibits 5-HT2CR function by interfering with the binding of 5-HT to the receptor. We could not determine the dual binding site of tramadol on 5-HT2CR, although it is essential to reveal the effect of tramadol on 5-HT receptors in detail. Moreover, it is not clear where 5-HT binds to 5-HT2C receptors. To answer these questions, it is necessary to investigate the region of 5-HT2C responsible for tramadol binding using chimera 5-HT2C or site-directed mutagenesis experiments, such as radio-ligand tramadol binding experiments.

The roles of 5-HT receptors in antinociception and analgesic actions have been investigated with a variety of approaches. 5-HT causes nociception (20,21). By contrast, several investigators have demonstrated that intrathecal serotonin induces antinociception in a variety of animal species (22,23). The role of serotonin signaling in pain sensation is still controversial. However, it has been reported that the peripheral nociceptive actions of IV administered 5-HT in the rat require dual activation of both 5-HT2 and 5-HT3 receptor subtypes (24), suggesting that 5-HT2CR participates in central pain procession. Inhibition of the function of 5-HT2CR by tramadol would modulate its antinociceptive effects. Conversely, some 5HT2 receptor antagonists have mood- and motivation-improving effects (25). Tramadol alters mood (26), and this effect is a result of inhibition of the function of 5-HT2CR. Moreover, 5-HT2CR mutant mice display both an epilepsy and obesity phenotype (27). Although these symptoms may be related to the inhibition of 5-HT2cR by tramadol (28), more animal studies are necessary to answer these questions.

In conclusion, our results suggest that tramadol inhibits 5-HT2CR function by competing for 5-HT binding sites. This suggests that the inhibition of 5-HT2CR function by tramadol explains one of the pharmacological properties of tramadol.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000; 60: 139–76.[Web of Science][Medline]
  2. Giusti P, Buriani A, Cima L, et al. Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes. Br J Pharmacol 1997; 122: 302–6.[Web of Science][Medline]
  3. Sagata K, Minami K, Yanagihara N, et al. Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg 2002; 94: 901–6.[Abstract/Free Full Text]
  4. Shiraishi M, Minami K, Uezono Y, et al. Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther 2001; 299: 255–60.[Abstract/Free Full Text]
  5. Shiga Y, Minami K, Shiraishi M, et al. The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors. Anesth Analg 2002; 95: 1269–73.[Abstract/Free Full Text]
  6. Gyermek L. Pharmacology of serotonin as related to anesthesia. J Clin Anesth 1996; 8: 402–25.[Web of Science][Medline]
  7. Saudou F, Hen R. 5-Hydroxytryptamine receptor subtypes: molecular and functional diversity. Adv Pharmacol 1994; 30: 327–80.[Medline]
  8. Rauser L, Savage JE, Meltzer HY, et al. Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine (2C) receptor. J Pharmacol Exp Ther 2001; 299: 83–9.[Abstract/Free Full Text]
  9. Niswender CM, Copeland SC, Herrick-Davis K, et al. RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 1999; 274: 9472–8.[Abstract/Free Full Text]
  10. Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995; 374: 542–6.[Medline]
  11. Minami K, Minami M, Harris RA. Inhibition of 5-hydroxytryptamine type 2A receptor-induced currents by n-alcohols and anesthetics. J Pharmacol Exp Ther 1997; 281: 1136–43.[Abstract/Free Full Text]
  12. Oliva P, Aurilio C, Massimo F, et al. The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 2002; 445: 179–85.[Web of Science][Medline]
  13. Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J, et al. Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine1A/1B antagonist, enhances the analgesic effect of tramadol. Pain 2000; 88: 119–24.[Web of Science][Medline]
  14. Harris RA, Mihic SJ, Dildy-Mayfield JE, et al. Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition. FASEB J 1995; 9: 1454–62.[Abstract]
  15. Pritchett DB, Bach AW, Wozny M, et al. Structure and functional expression of cloned rat serotonin 5HT-2 receptor. EMBO J 1988; 7: 4135–40.[Web of Science][Medline]
  16. Minami K, Shiraishi M, Uezono Y, et al. The inhibitory effects of anesthetics and ethanol on substance P receptors expressed in Xenopus oocytes. Anesth Analg 2002; 94: 79–83.[Abstract/Free Full Text]
  17. Minami K, Vanderah TW, Minami M, et al. Inhibitory effects of anesthetics and ethanol on muscarinic receptors expressed in Xenopus oocytes. Eur J Pharmacol 1997; 339: 237–44.[Web of Science][Medline]
  18. Toullec D, Pianetti P, Coste H, et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 1991; 266: 15771–81.[Abstract/Free Full Text]
  19. Lintz W, Barth H, Osterloh G, et al. Bioavailability of enteral tramadol formulations [in German]. Arzneimittelforschung 1986; 36: 1278–83.[Medline]
  20. Fock S, Mense S. Excitatory effects of 5-hydroxytryptamine, histamine and potassium ions on muscular group IV afferent units: a comparison with bradykinin. Brain Res 1976; 105: 459–69.[Web of Science][Medline]
  21. Lang E, Novak A, Reeh PW, et al. Chemosensitivity of fine afferents from rat skin in vitro. J Neurophysiol 1990; 63: 887–901.[Abstract/Free Full Text]
  22. Yaksh TL, Wilson PR. Spinal serotonin terminal system mediates antinociception. J Pharmacol Exp Ther 1979; 208: 446–53.[Free Full Text]
  23. Schmauss C, Hammond DL, Ochi JW, et al. Pharmacological antagonism of the antinociceptive effects of serotonin in the rat spinal cord. Eur J Pharmacol 1983; 90: 349–57.[Web of Science][Medline]
  24. Meller ST, Lewis SJ, Brody MJ, et al. The peripheral nociceptive actions of intravenously administered 5-HT in the rat require dual activation of both 5-HT2 and 5-HT3 receptor subtypes. Brain Res 1991; 561: 61–8.[Web of Science][Medline]
  25. Lesch KP, Aulakh CS, Murphy DL. Brain serotonin subsystem complexity and receptor heterogeneity: therapeutic potential of selective serotonin agonists and antagonists. Psychopharmacology Ser 1993; 10: 52–69.
  26. Pinkofsky HB, Woodward RA, Reeves RR. Mood alterations and tramadol. Am J Psychiatry 1996; 153: 843–4.
  27. Heisler LK, Chu HM, Tecott LH. Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann NY Acad Sci 1998; 861: 74–8.[Web of Science][Medline]
  28. Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000; 20: 1423–31.[Web of Science][Medline]
Accepted for publication November 6, 2003.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
R. Marincsak, B. I. Toth, G. Czifra, T. Szabo, L. Kovacs, and T. Biro
The Analgesic Drug, Tramadol, Acts as an Agonist of the Transient Receptor Potential Vanilloid-1
Anesth. Analg., June 1, 2008; 106(6): 1890 - 1896.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ogata, J.
Right arrow Articles by Ueta, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ogata, J.
Right arrow Articles by Ueta, Y.
Related Collections
Right arrow Mechanisms
Right arrow Pain
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press