Vol. 289, Issue 1, 417-426, April 1999

Antinociceptive Properties of the New Alkaloid, cis-8,10-Di-N-Propyllobelidiol Hydrochloride Dihydrate Isolated from Siphocampylus verticillatus: Evidence for the Mechanism of Action¹

Adair R. S. Santos, Obdúlio G. Miguel, Rosendo A. Yunes and João B. Calixto

Department of Pharmacology, Center of Biological Science (A.R.S.S., J.B.C.) and Department of Chemistry, Center of Physical and Mathematical Sciences (O.G.M., R.A.Y.), Universidade Federal de Santa Catarina, Florianópolis, 88049-900, Brazil

The antinociceptive action of the alkaloid cis-8,10-di-n-propyllobelidiol hydrochloride dehydrate (DPHD), isolated from Siphocampylus verticillatus, given i.p., p.o., i.t., or i.c.v., was assessed in chemical and thermal models of nociception in mice, such as acetic acid-induced abdominal constriction, formalin- and capsaicin-induced licking, and hot-plate and tail-flick tests. DPHD given by i.p., p.o., i.t., or i.c.v. elicited significant and dose-related antinociception. At the ID₅₀ level, DPHD was about 2- to 39-fold more potent than aspirin and dipyrone, but it was about 14- to 119-fold less potent than morphine. Its analgesic action was reversed by treatment of animals with p-chlorophenylalanine, naloxone, cyprodime, naltrindole, nor-binaltrorphimine, L-arginine, or pertussis toxin. Its action was also modulated by adrenal-gland hormones but was not affected by -aminobutyric acid type A or type B antagonist, bicuculine, or phaclofen, nor was it affected by glibenclamide. DPHD, given daily for up to 7 days, did not develop tolerance to itself nor did it induce cross-tolerance to morphine. However, animals 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 transit in mice, nor did it inhibit electrical field stimulation of the guinea pig ileum or mouse vas deferens in vitro. Thus, DPHD produces dose-dependent and pronounced systemic, spinal, and supraspinal antinociception in mice, including against the neurogenic nociception induced by formalin and capsaicin. Its antinociceptive effect involves multiple mechanisms of action, namely interaction with µ, , or  opioid systems, L-arginine-nitric oxide and serotonin pathways, activation of G_i protein sensitive to pertussis toxin, and modulation by endogenous glucocorticoids.