Pharmacological studies of lappaconitine: supraspinal-spinal interaction in antinociception.

Changes in lappaconitine levels in blood, brain and spinal cord following subcutaneous (s.c.) injection were correlated with the analgesic activity at intervals up to 90 minutes after injection. In the mouse, intracerebroventricular (i.c.v.) and intrathecal (i.t.) injections of amounts corresponding to ED50 values in the tail pinch method (i.c.v.: 2333 ng/mouse; i.t.: 1127 ng/mouse) gave peak lappaconitine levels of 1300 ng/g brain and 761 ng/g spinal cord, respectively. However, injection of lappaconitine at ED50 by the s.c. route (7 mg/kg) gave lower peak lappaconitine levels of 320 ng/g brain and 214 ng/g spinal cord. The responses to i.c.v., i.t. and combined i.c.v. plus i.t. administration of lappaconitine were evaluated by the determination of ED50 values, which were plotted as an isobologram. The experimental point is not significantly different from the theoretical additive ED50 point. When a dose equal to the experimental additive ED50 value (i.c.v., i.t. = 620, 413 ng/mouse) was injected, peak lappaconitine levels reached 344 ng/g brain and 241 ng/g spinal cord. Thus, the equianalgesic doses of lappaconitine (ED50 by the s.c. route and additive ED50 by the i.c.v. plus i.t. route) gave closely similar concentrations of the drug in brain and spinal cord. These results indicate that a simultaneous action of lappaconitine on supraspinal and spinal sites is likely to be important for the analgesia produced by systemically administered lappaconitine.