Augmented analgesic effect of tyramine or octopamine in combination with lidocaine is mediated with α-adrenergic receptors

Although norepinephrine is known to enhance the antinociceptive effect of the local anesthetic lidocaine, the effects of two precursors of norepinephrine, tyramine and octopamine, on the antinociceptive potency of lidocaine are not known. We aimed to investigate cutaneous antinociceptive interactions and mechanism of action of tyramine and octopamine, and their respective coinjections with lidocaine, in comparison with norepinephrine. Cutaneous nociceptive blockade in rats was quantified by the blockage of cutaneous trunci muscle reflexes induced by needle pinpricks. Isobolographic analysis was used to estimate the interactions between lidocaine and drugs (tyramine, octopamine, or norepinephrine). Phentolamine was added to a two-drug combination. At ED₇₅ (75% effective dose), subcutaneous injection of tyramine and lidocaine provoked 73% and 77% nociceptive blockade. After isobolographic analysis, the theoretical 50% effective dose (ED₅₀) was significantly greater than the experimental ED₅₀ in both octopamine-lidocaine combination and norepinephrine-lidocaine combination (<i>P</i> < 0.01), but not in tyramine-lidocaine combination. Lidocaine (ED₉₅) in combination with tyramine (30 µmole), octopamine (12 µmole), or norepinephrine (0.007 µmole) prolonged the duration of nociceptive blockade (<i>P</i> < 0.05). The addition of phentolamine (0.06 µmole) to a combination of tyramine (30 µmole) and lidocaine (ED₉₅), a combination of octopamine (12 µmole) and lidocaine (ED₉₅), or a combination of norepinephrine (0.007 µmole) and lidocaine (ED₉₅) showed a nociceptive blocking effect similar to that of lidocaine (ED₉₅) alone. Tyramine and octopamine presented dose-dependent cutaneous nociceptive blockades. Tyramine-lidocaine combination produced an additive effect. The combination of octopamine-lidocaine and norepinephrine-lidocaine showed synergistic effects that were inhibited by phentolamine, suggesting that this synergistic effect is mediated with α-adrenergic receptors.<b>NEW & NOTEWORTHY</b> Tyramine and octopamine prolonged the duration of cutaneous nociceptive blockades by lidocaine. We have identified a new mechanism that augmented analgesic effect of tyramine or octopamine in combination with lidocaine is mediated with α-adrenergic receptors.