Vonvoigtlander P F, Lewis R A
Upjohn Company, Kalamazoo, Michigan 49001.
Drug Des Deliv. 1987 Dec;2(2):129-33.
The analgesic activity of tazadolene succinate was assessed in mice and rats subsequent to pretreatment with various depletors and antagonists of monoamine neurotransmitters. In the mouse warm plate assay, reserpine was confirmed to cause a profound antagonism of tazadolene analgesia. However, yohimbine, Sch 23390 and haloperidol, antagonists of alpha 2 adrenergic, D1 dopaminergic and D2 dopaminergic receptors respectively, did not block tazadolene, nor did the serotonin depletor, p-chlorophenylalanine. But mice treated with both the depletor and yohimbine were significantly resistant to the analgesic effects of tazadolene. Combined treatments of haloperidol or prazosin (an alpha1 adrenergic antagonist) and p-chlorophenylalanine were not similarly effective. In the rat, reserpine blocked tazadolene analgesia in both the hot plate and air induced writhing assays. Likewise, combined treatment with yohimbine and p-chlorophenylalanine also antagonized the analgesia. These results confirm the monoamine dependence of tazadolene analgesia and indicate that both serotonergic and alpha 2 adrenergic mechanisms are involved. The results further suggest that these systems may be in parallel and integrated such that either one is capable of the primary expression of the analgesic effect of tazadolene. Thus, the unique analgesia properties of tazadolene are apparently due to the ability of this compound to activate both serotonergic and alpha 2 adrenergic antinociceptive systems.
