Background and objectives: Intraspinally administered alpha 2-adrenergic agonists produce analgesia in part by causing spinal acetylcholine and nitric oxide (NO) release. Clonidine-induced analgesia is enhanced by subarachnoid neostigmine and inhibited by N-methyl-L-arginine (NMLA), a blocker of NO synthesis. The authors tested whether dexmedetomidine, an alpha 2-adrenergic agonist with greater intrinsic efficacy than clonidine, would be similarly affected by neostigmine and NMLA.
Methods: Drugs were administered subarachnoid to 22 chronically prepared ewes, and antinociception was determined by a noxious mechanical stimulation. Sheep received subarachnoid saline, neostigmine, or NMLA, followed by cumulative doses of clonidine or dexmedetomidine. Neostigmine was injected either 20 or 60 minutes prior to beginning cumulative dosing with the alpha 2-adrenergic agonist.
Results: Both clonidine and dexmedetomidine produced dose-dependent antinociception with similar potency (ED50 was 61 +/- 26 micrograms for clonidine and 65 +/- 24 micrograms dexmedetomidine). Neostigmine pretreatment 20 minutes before dosing potentiated clonidine's dose response (ED50 was reduced to 6.8 +/- 2.3 micrograms), but had no effect on dexmedetomidine (ED50 27 +/- 6.1 micrograms). Neostigmine pretreatment 60 minutes before dosing potentiated both clonidine (ED50 was reduced to 11.8 +/- 5.1 micrograms) or dexmedetomidine (ED50 was reduced to 10 +/- 2.1 micrograms). The NMLA did not affect antinociception from dexmedetomidine.
Conclusions: These data are in agreement with previous hemodynamic studies suggesting that neostigmine has a slow onset of action after subarachnoid administration. That clonidine is potentiated more than dexmedetomidine by neostigmine pretreatment at 20 minutes likely may reflect the lower intrinsic efficacy of clonidine. Alternatively, since acetylcholine can cause NO synthesis, lack of effect of NMLA on dexmedetomidine implies that analgesia from this drug is less reliant on acetylcholine-NO mechanisms than clonidine. The large potentiation observed between neostigmine and these alpha 2-adrenergic agonists carries important clinical implications.