grunenthal.de

The present study was conducted to characterise the centrally active analgesic drug tramadol hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)-methyl]-1-(3-methoxyphenyl)-cyclohe xanol hydrochloride] and its metabolites M1, M2, M3, M4 and M5 at the cloned human mu-opioid receptor. Membranes from stably transfected Chinese hamster ovary (CHO) cells were used to determine the four parameters of the ligand-receptor interaction: the affinity of (+/-)-tramadol and its metabolites was determined by competitive inhibition of [3H]naloxone binding under high and low salt conditions. The agonist-induced stimulation of [35S]GTPgammaS binding permits the measurement of potency (EC50), efficacy (Emax = maximal stimulation) and relative intrinsic efficacy (effect as a function of receptor occupation). The metabolite (+)-M1 showed the highest affinity (Ki=3.4 nM) to the human mu-opioid receptor, followed by (+/-)-M5 (Ki=100 nM), (-)-M1 (Ki=240 nM) and (+/-)-tramadol (Ki=2.4 microM). The [35S]GTPgammaS binding assay revealed an agonistic activity for the metabolites (+)-M1, (-)-M1 and (+/-)-M5 with the following rank order of intrinsic efficacy: (+)-M1>(+/-)-M5>(-)-M1. The metabolites (+/-)-M2, (+/-)-M3 and (+/-)-M4 displayed only weak affinity (Ki> 10 microM) and had no stimulatory effect on GTPgammaS binding. These data indicate that the metabolite (+)-M1 is responsible for the mu-opioid-derived analgesic effect.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10961373&dopt=Abstract tramadol Ultram

unav.es

The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethyltramadol [(+)-M1] and (-)-O-desmethyltramadol [(-)-M1], main metabolites of tramadol, was studied in three groups of rats. (+)-M1 and (-)-M1, both with different pd properties, were studied under steady-state and nonsteady-state conditions, depending on the group. Plasma drug concentration and antinociception were simultaneously measured in each animal by using an enantioselective analytical assay and the tail-flick test, respectively. Respiratory depression also was evaluated in another series of experiments according to the same experimental conditions. The pk behavior was similar for both enantiomers and no significant (P >.05) interaction between two compounds was found at this level. However, a significant (P <.01) potentiation in the antinociceptive effect elicited by (+)-M1 was found during and after (-)-M1 administration. The pd model used to describe the time course of the antinociception in the presence of (+)-M1, (-)-M1, or both is based on previous knowledge of the compounds and includes the following: 1) an effect compartment model to account for the opioid effect of (+)-M1, and 2) an indirect response model accounting for the release of noradrenaline (NA) caused by (+)-M1, and the inhibition of the NA reuptake due to the action of (-)-M1. The model predicts a positive contribution to antinociception of the predicted increasing levels of NA. No significant (P >.05) respiratory effects were seen during or after (+)-M1 and (-)-M1 administration.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10992001&dopt=Abstract tramadol Ultram




Eksp Klin Farmakol. 2000 Jul-Aug;63(4):7-12.
[Effects of opioid analgesics on potential-gated ion channels in the pond snail neurons]

[Article in Russian]

Vislobokov AI, Savos'kin AL.

Valdman Institute of Pharmacology, Pavlov State Medical University, St. Petersburg, Russia.

The effects of opioid analgesics morphine, promedol, tramadol, and butorphanol on the transmembrane calcium, sodium, and potassium (fast and slow) ion currents in pond snail (Lymnaea stagnalis) neurons were studied by intracellular dialysis and membrane potential (voltage-clamp) measurements. It was established that all these drugs produce a dose-dependent reversible inhibition of the ion currents (sodium calcium potassium) and reduce nonspecific leak currents, thus producing a stabilizing action upon the sample membrane. The current-inhibiting effect of morphine was not eliminated by naloxone (500 microM); moreover, the latter drug significantly inhibited the ion currents as well.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11022297&dopt=Abstract tramadol Ultram




J Chromatogr B Biomed Sci Appl. 2000 Aug 18;745(2):271-8.
Assay of tramadol in urine by capillary electrophoresis using laser-induced native fluorescence detection.

Soetebeer UB, Schierenberg MO, Schulz H, Grunefeld G, Andresen P, Blaschke G.

Institute of Pharmaceutical Chemistry, University of Munster, Germany.

Capillary electrophoresis (CE) with UV laser-induced native fluorescence detection was developed as a sensitive and selective assay for the direct determination of tramadol in human urine without extraction or preconcentration. The main problem in CE is the small inner diameter of the capillary which causes a low sensitivity with instruments equipped with a UV detector. Laser-induced native fluorescence with a frequency doubled argon ion laser at an excitation wavelength of 257 nm was used for the direct assay of tramadol in urine to enhance the limit of detection about 1,000-fold compared to UV absorption detection. The detection system consists of an imaging spectrograph and an intensified CCD camera, which views an illuminated 1.5 mm section of the capillary. This set-up is able to record the whole emission spectra of the analytes to achieve additionally wavelength-resolved electropherograms. In the concentration range of 20 ng/ml-5 microg/ml in human urine coefficients of correlation were better than 0.998. Within-day variation determined on four different concentrations showed accuracies ranging from 90.2 to 108.4%. The relative standard deviation (RSD) was determined to be less than 10%. Day-to-day variation presented accuracies ranging from 90.9 to 103.1% with an RSD less than 8%.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11043746&dopt=Abstract tramadol Ultram




Pain. 2000 Nov;88(2):119-24.
Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol.

Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J, Roca-Vinardell A, Mico JA.

Department of Neuroscience, Neuropsycopharmacology Unit, University of Cadiz, Plz. Fragela 9, 11003 Cadiz, Spain.

The ability of pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, to enhance the clinical antidepressant response to selective serotonin re-uptake inhibitors is generally attributed to a blocking of the feedback that inhibits the serotoninergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to enhance the analgesic effect of tramadol, an atypical centrally-acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the re-uptake of 5-HT in the raphe nuclei. Racemic pindolol (2 mg/kg, s.c.), rendered analgesic a non-effective acute dose of tramadol (10-40 mg/kg, i.p.) in two nociceptive tests: a hot plate test in mice and a plantar test in rats. Moreover, (+/-)8-OH-DPAT (0.125-1 mg/kg, s.c.), a selective 5-HT(1A) agonist, reduces the analgesic effect of tramadol in the same tests. These results suggest an implication of the somatodendritic 5-HT(1A) receptors in the analgesic effect of tramadol and open a new adjuvant analgesic strategy for the use of this compound.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11050366&dopt=Abstract tramadol Ultram