naloxone and zomepirac

D-Phenylalanine, along with morphine, acetylsalicylic acid and zomepirac sodium were evaluated for their antinociceptive actions in monkeys (M. fascicularis) trained to autoregulate nociceptive stimulation using a discrete-trials, aversive-threshold paradigm. Morphine sulfate produced dose-related increases in aversive threshold which were reversible after administration of naloxone (12.5 or 25 micrograms/kg i.m.). D-Phenylalanine (500 mg/kg p.o.) produced a small increase in aversive threshold which was not statistically significant and not naloxone reversible. Acetylsalicylic acid (200 mg/kg p.o.) but not zomepirac sodium (200 mg/kg p.o.) in combination with D-phenylalanine (500 mg/kg) produced a small statistically significant increase in aversive threshold. Our results argue against the hypothesis that D-phenylalanine is responsible for increasing aversive thresholds via opiate receptor mechanisms involving increased activity of enkephalins at synaptic loci. Previous studies by others in rats and mice showed that D-phenylalanine and acetylsalicylic acid produced increases in nociceptive thresholds which were naloxone reversible. Our failure to find opiate receptor mediated analgesia in a primate model with demonstrated opiate receptor selectivity and sensitivity is discussed in terms of previous basic and clinical research indicating an analgesic role for D-phenylalanine. Possible species difference in drug action is discussed in terms of inhibition by D-phenylalanine of carboxy-peptidase-like enkephalin processing enzymes as well as inhibition of carboxypeptidase-like enkephalin degrading enzymes.

Topics: Animals; Aspirin; Avoidance Learning; Carboxypeptidases; Drug Interactions; Isomerism; Macaca fascicularis; Male; Morphine; Naloxone; Neprilysin; Pain; Phenylalanine; Protease Inhibitors; Sensory Thresholds; Tolmetin

Zomepirac sodium inhibited the reflex hypertension caused by an injection of bradykinin into the splenic artery of anaesthetized dogs, but not that by injection of bradykinin plus PGE1. In the rat acetic acid writhing test, the potency ratio of intraperitoneal (ED50 = 0.41 microgram/kg) to intravenous (ED50 = 33.5 micrograms/kg) anti-writhing activity of zomepirac sodium was 79.2 (37.1-173), though the ratio of codeine phosphate (373 micrograms/kg, i.p., 352 micrograms/kg, i.v.) was 0.934. When equipotent doses of zomepirac sodium were administered to rats receiving intraperitoneally acetic acid, the plasma zomepirac level after i.v. administration was more than 200 times that after i.p. administration, while the peritoneal exudate zomepirac contents were nearly equal after administration by both routes. Zomepirac sodium (5 micrograms/kg) did not produce significant anti-writhing activity after intracerebroventricular administration. From these results, it was suggested that zomepirac sodium produced analgesic action through a strong blockade of the hyperalgesia in the peripheral system.

Topics: Alprostadil; Analgesics; Animals; Ascitic Fluid; Bradykinin; Dogs; Hypertension; Injections, Intraventricular; Male; Naloxone; Pain; Prostaglandins E; Pyrroles; Rats; Rats, Inbred Strains; Tolmetin

Zomepirac, an inhibitor of prostaglandin biosynthesis, was evaluated for analgesic activity in a number of pharmacological screens. In the acetylcholine writhing test, zomepirac was found to be more potent than codeine, pentazocine, aspirin, and acetaminophen and equivalent in potency to morphine. Zomepirac was inactive in a number of tests that detect narcotic agents, suggesting that the drug will not induce physical dependence. The possibility of a central nonnarcotic as well as a peripheral analgesic mechanism merits consideration.

Topics: Analgesics; Animals; Cattle; Cyclooxygenase Inhibitors; Drug Interactions; Hindlimb; Humans; In Vitro Techniques; Male; Mice; Morphine; Naloxone; Platelet Aggregation; Pyrroles; Reaction Time; Receptors, Opioid; Substance-Related Disorders; Tolmetin