Tapentadol HCl [(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] is a novel dual mode analgesic with µ-opioid receptor (MOR) agonism and norepinephrine (NE) reuptake inhibition. The compound had a K_i of 0.1 µM in a rat MOR binding assay, and a relative efficacy of 88% (compared to morphine) in a functional [³⁵S]GTPγS binding assay. There was at least 10-fold selectivity over other opioid receptors (delta, kappa, ORL1). In addition, tapentadol HCl inhibited the NE reuptake transporter with a K_i of 0.5 µM (in a rat synaptosomal reuptake assay). In vivo brain microdialysis studies in the ventral hippocampus of freely moving rats showed that tapentadol HCl produces large increases in extracellular levels of NE (up to 450% above baseline) in the analgesic dose range, confirming the functional in vivo relevance of the NE transporter inhibition. In contrast, the prototypical opioid morphine produced only marginal effects on NE levels. The noradrenergic contribution to the dual mode of action of tapentadol HCl was demonstrated in the spinal nerve ligation rat model of chronic neuropathic pain. Equianalgesic doses of tapentadol HCl and morphine were combined with fixed doses of the α₂-NE receptor antagonist yohimbine and the MOR antagonist naloxone. It was found that the analgesic effect of tapentadol HCl was strongly antagonized by yohimbine but only weakly affected by naloxone, whereas the opposite was the case for morphine. The greater sensitivity of morphine analgesia towards naloxone antagonism was confirmed in the mouse phenylquinone writhing model, where naloxone antagonized the analgesic effect of morphine much more potently than the analgesic effect of tapentadol HCl, implying an additional naloxone-insensitive component in the latter drug. Taken together, the data support the suggestion that the broad analgesic profile of tapentadol HCl is based on the combination of MOR activation and NE reuptake inhibition.