Antinociceptive properties of the new alkaloid, cis-8,10-di-N-propyllobelidiol hydrochloride dihydrate isolated from Siphocampylus verticillatus: Evidence for the mechanism of action

The antinociceptive action of the alkaloid cis-8,10-di-n-propyllobelidiol h ydrochloride dehydrate (DPHD), isolated from Siphocampylus verticillatus, g iven i.p., p.o., i.t., or i.c.v., was assessed in chemical and thermal mode ls of nociception in mice, such as acetic acid-induced abdominal constricti on, formalin- and capsaicin-induced licking, and hot-plate and tail-flick t ests. DPHD given by i.p., p.o., i.t., or i.c.v. elicited significant and do se-related antinociception. At the ID,, level, DPHD was about 2- to 39-fold more potent than aspirin and dipyrone, but it was about 14- to 119-fold le ss potent than morphine. Its analgesic action was reversed by treatment of animals with p-chlorophenylalanine, naloxone, cyprodime, naltrindole, norbi naltrorphimine, L-arginine, or pertussis toxin. Its action was also modulat ed by adrenal-gland hormones but was not affected by gamma-aminobutyric aci d type A or type B antagonist, bicuculine, or phaclofen, nor was it affecte d by glibenclamide. DPHD, given daily for up to 7 days, did not develop tol erance to itself nor did it induce cross-tolerance to morphine. However, an imals rendered tolerant to morphine presented cross-tolerance to DPHD. The antinociception of DPHD was not secondary to its anti-inflammatory effect, nor was it associated with nonspecific effects such as muscle relaxation or sedation. DPHD, in contrast to morphine, did not decrease charcoal meal tr ansit in mice, nor did it inhibit electrical field stimulation of the guine a pig ileum or mouse vas deferens in vitro. Thus, DPHD produces dose-depend ent and pronounced systemic, spinal, and supraspinal antinociception in mic e, including against the neurogenic nociception induced by formalin and cap saicin. Its antinociceptive effect involves multiple mechanisms of action, namely interaction with mu, delta, or kappa opioid systems, L-arginine-nitr ic oxide and serotonin pathways, activation of Gi protein sensitive to pert ussis toxin, and modulation by endogenous glucocorticoids.