Hagen-Heinrich Hennies

(–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): a Novel μ-Opioid Receptor Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties

(–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel μ-opioid receptor (MOR) agonist (Ki = 0.1 μM; relative efficacy compared with morphine 88% in a [35S]guanosine 5′-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 μM for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (+450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the α2-adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.

Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol

Tramadol is a centrally acting analgesic with low affinity to opioid receptors. A further mode of action is inhibition of noradrenaline uptake as measured in standard assays. Since tramadol shows antinociception at the spinal site, it was to be tested whether uptake blockade could be verified in spinal tissue. Therefore, synaptosomes and slices had to be prepared from the dorsal half of the spinal cord and the uptake of [3H]noradrenaline into synaptosomes to be characterized. The uptake was linear for at least 3 min. The apparent Km was 0.16 microM and Vmax was 7.9 pmol/min/mg protein. Tramadol inhibited the uptake competitively as analysed with Dixon plots with a Ki of 0.6 microM. Uptake inhibition was effected in order of potency by (+)-oxaprotiline > nisoxetine > (-)-tramadol > (-)-oxaprotiline = tramadol > (+)-tramadol. Slices were preincubated with [3H]noradrenaline then superfused and stimulated electrically. Nisoxetine, tramadol and its (-)-enantiomer enhanced mainly the stimulation-evoked overflow indicating uptake inhibition without releasing effects. Experiments with inclusion of the noradrenaline uptake inhibitor desipramine provided evidence that tramadol interfered with the noradrenaline transporter. The results show that spinal synaptosomes and slices are valid preparations to study local noradrenaline uptake and release. Tramadol enhances extraneuronal noradrenaline levels in the spinal cord by competitive interference with the noradrenaline uptake mechanism.

Galanin receptor antagonists attenuate spinal antinociceptive effects of DAMGO, tramadol and non-opioid drugs in rats

The involvement of endogenous galanin to antinociception elicited by intrathecally (i.t.) or systemically administered drugs from different chemical and therapeutic classes was investigated using the rat Randall-Selitto or the rat tail-flick test, in the absence or presence of the i.t. administered galanin receptor antagonists galantide and M-35. Antinociception elicited by i.t. tramadol (24 micrograms), DAMGO (1 microgram), clonidine (48 micrograms), desipramine (6 micrograms) or fenfluramine (60 micrograms) was attenuated by i.t. galantide (2 micrograms); the attenuation reached significance at least at one time point. A partial antagonism by i.t. galantide was also observed against the antinociception of i.p. tramadol (10 mg/kg), i.v. clonidine (1 mg/kg), i.p. desipramine (1 mg/kg), or i.p. dipyrone (1000 mg/kg), but antinociception by i.p. fenfluramine (30 mg/kg) was not affected. Using M-35 (2 micrograms i.t.), the antinociception of i.t. tramadol or DAMGO was attenuated, but no inhibition was observed when clonidine, desipramine or fenfluramine were used i.t. If drugs were administered systemically, only antinociception of i.p. fenfluramine but not that of i.p. tramadol, or i.v. clonidine, or i.p. desipramine or i.p dipyrone was attenuated. In the rat tail flick test, co-injection of either 2 micrograms i.t. galantide or M-35 with i.t. tramadol (12 micrograms) almost abolished the antinociceptive effect, whereas the antinociception of systemically administered tramadol (4.6 mg/kg i.p.) was only partially attenuated by i.t. galantide and not affected by i.t. M-35. Binding studies in dorsal spinal cord tissue showed no affinity of galantide or M-35 to spinal mu-, or delta-, or kappa-opioid receptors and none of the other drugs interfered with the spinal galanin binding site. These data give further support of at least a partial galanin link in spinal processes of antinociception.