Spinal-Supraspinal and Intrinsic m-Opioid Receptor Agonist-Norepinephrine Reuptake Inhibitor (MOR-NRI) Synergy of Tapentadol in Diabetic Heat Hyperalgesia in Mice

Tapentadol is a m-opioid receptor (MOR) agonist and norepi-nephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interac-tion of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1–3.16 mg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED50 0.42 mg/animal i.t., 0.18 mg/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED50 0.053 mg/animal i.t. 1 i.c.v.). Morphine (0.001–10 mg/animal) also showed central efficacy and synergy (ED50 0.547 mg/animal i.t., 0.004 mg/animal i.c.v.