Synephrine potentiates lidocaine‐induced cutaneous analgesia via α‐adrenergic receptors in male rats

This study aimed to assess the cutaneous analgesic effect of the lidocaine-synephrine combination and its underlying α-adrenergic receptor-mediated mechanism in comparison with phenylephrine. Cutaneous analgesia after subcutaneous drug injection was assessed by inhibition of the cutaneous trunci muscle reflex in response to needle pinpricks on the shaved dorsal skin of Sprague-Dawley rats. Synephrine, like the local anesthetic lidocaine, is capable of inducing cutaneous analgesia but is less potent. On an equipotent basis (ED₂₅, ED₅₀ [50% effective dose], and ED₇₅), the block duration induced by synephrine or phenylephrine was longer than that induced by lidocaine (p < 0.01). When combined with lidocaine, the ED₅₀ for synephrine decreased from 326 (183-579) μmol/kg to 141 (128-156) μmol/kg (p < 0.01), and for phenylephrine, it decreased from 15.8 (9.0-27.9) μmol/kg to 6.2 (5.9-6.6) μmol/kg (p < 0.01). Lidocaine (ED₉₅) in combination with either synephrine (52 μmol/kg) or phenylephrine (1.6 μmol/kg) prolonged the duration of action (p < 0.001), while phentolamine (0.3 μmol/kg) reversed these effects. We concluded that synephrine produces dose-dependent cutaneous analgesia that is less potent but longer-lasting than lidocaine. The enhanced analgesic effects of the lidocaine-synephrine and lidocaine-phenylephrine combinations are mediated through α-adrenergic receptor activation.