The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice.

Activation of the μ-opioid receptor (MOR) and noradrenaline reuptake inhibition (NRI) are well recognized as analgesic principles in acute and chronic pain indications. The novel analgesic tapentadol combines MOR agonism and NRI in a single molecule. The present study used OPRM1 (MOR) knockout (KO) mice to determine the relative contribution of MOR activation to tapentadol-induced analgesia in models of acute (nociceptive) and chronic (neuropathic) pain. Antinociceptive efficacy was inferred from paw withdrawal latencies on a 48 °C hot plate in naive animals. Antihyperalgesic efficacy was inferred from the number of nocifensive reactions in diabetic animals (streptozotocin-induced) and non-diabetic controls on a 50 °C hot plate. The effect of tapentadol (0.316-31.6 mg/kg IP) and the MOR agonist morphine (3-10 mg/kg IP) was determined in OPRM1 KO- and congenic wildtype mice. At baseline, diabetic OPRM1 KO mice showed reduced nocifensive reactions as compared to diabetic wildtype mice. In both pain models, morphine and tapentadol were effective in wildtype mice. In the KO mice, however, morphine failed to produce analgesia in either model. On the other hand, tapentadol still had clear effects, and when tested at a dose that was fully efficacious in wildtype mice, showed reduced but still significant antinociceptive efficacy in non-diabetic, and antihyperalgesic efficacy in diabetic OPRM1 KO mice. The remaining antinociceptive activity of tapentadol in OPRM1 KO mice was abolished by the α₂-adrenoceptor antagonist yohimbine. In OPRM1 wildtype mice, the antihyperalgesic effect of tapentadol was 10 times more potent in diabetic animals (ED₅₀=1.10 mg/kg) than its antinociceptive effect in naïve animals (ED₅₀=10.8 mg/kg). This study supports the conclusion that the analgesic effect of tapentadol is only partly due to the activation of MOR, both under acute and chronic pain conditions, and that the efficacy of tapentadol against acute and chronic pain is based on its combined mechanism of action.