Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests. Study of the mechanism of action.
Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 micromol/kg, and 2.6 and 1.2 micromol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 micromol/site, and 0.4 and 0.9 micromol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 micromol/kg, 2.2 micromol/paw, 0.4 micromol/site and 0.14 micromol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 micromol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, L-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the L-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin. interaction of ATP-sensitive K+ channels, GABA(B) receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.
Beirith
A
A
Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
Santos
A R
AR
Rodrigues
A L
AL
Creczynski-Pasa
T B
TB
Calixto
J B
JB
D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin; D004177:Dipyrone / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005557:Formaldehyde; D018698:Glutamic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D005557:Formaldehyde; D018698:Glutamic Acid; D004177:Dipyrone; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D002211:Capsaicin