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

Abstract

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 co-injections 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 employed 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 ED₅₀ was significantly greater than the experimental ED₅₀ in both octopamine-lidocaine combination and norepinephrine-lidocaine combination (p<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 (p<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 n orepinephrine (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 was inhibited by phentolamine, suggesting that this synergistic effect is mediated with alpha-adrenergic receptors.