Synergistic Interaction between the Two Mechanisms of Action of Tapentadol in Analgesia

The novel centrally acting analgesic tapentadol [(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail-flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action

Bringing the Outside In: Somaliland, Statebuilding, and Dual Hybridity

International norms of what it means to be a state dictate domestic policy within developing and unrecognized states but must co-exist with internal demands. With a mutual dependence between internal and external considerations and, indeed, legitimacy, at the fore of Somaliland’s statebuilding project and its stability, it is a useful study in achieving ‘success’ in statebuilding and in what success can mean in bringing together internal and external demands. This article examines the impact of the hybrid inclusion of traditional authority in the central democratic government as the marriage between internal and external demands. This article argues that the Somaliland state is successful because it is a flexible process rather than a project; a process that reflects the demands and expectations of society, an aspect that is often absent in statebuilding projects