cp-99994 and Acute-Disease

Animal studies suggest that substance P, a peptide that preferentially activates the neurokinin-1 (NK1) receptor, is involved in pain transmission, with particular importance in pain after inflammation.. The analgesic efficacy of CP-99,994, a NK1 receptor antagonist, was compared with ibuprofen and placebo in 78 subjects undergoing third molar extraction. The initial 60 subjects randomly received 1 of 3 possible treatments in a double-blind fashion before oral surgery: 750 microg/kg CP-99,994 infused intravenously over 5 hours on a tapering regimen starting 2 hours before surgery, 600 mg oral ibuprofen 30 minutes before surgery, or placebo. In a second study, 18 subjects were randomized to the same regimens starting 30 minutes before surgery to maximize the amount of CP-99,994 circulating during pain onset.. In the first study, ibuprofen significantly reduced pain, as measured by visual analog scale, from 90 to 240 minutes postoperatively compared with placebo. CP-99,994 produced analgesia that was significant at 90 minutes (P < 0.01 compared with placebo), but not at subsequent time points. In the second study, ibuprofen and, to a lesser extent, CP-99,994 significantly suppressed pain in comparison to placebo at 60, 90, and 120 minutes (P < 0.05). The incidence of side effects was similar across groups.. This replicate demonstration that a NK1 receptor blocker relieves clinical pain supports the hypothesis that substance P contributes to the generation of pain in humans. The reduction in postoperative pain at doses not producing side effects suggests that NK1 antagonists may be clinically useful.

Topics: Acute Disease; Analgesics; Double-Blind Method; Humans; Neurokinin-1 Receptor Antagonists; Pain Measurement; Pain, Postoperative; Piperidines; Time Factors; Tooth Extraction; Treatment Outcome

Substance P (SP) acting at the NK-1 neurokinin receptor has a well-documented role in the transmission and maintenance of nociceptive information. SP is found in the majority of fibers innervating the pancreas, and it is up-regulated after pancreatic inflammation. The aim of this study was to investigate the role of the NK-1 receptors in the maintenance of pancreatic nociception. Using a newly developed rat model of acute pancreatic nociception that persists for 1 week, the NK-1 receptor expression in the spinal cord and pancreas was examined using immunohistochemistry and Western blotting procedures. The effects of a specific NK-1 antagonist, CP99,994, on the behavioral manifestations of pancreatic nociception were determined. The antagonist was administered intraperitoneally and intrathecally to differentiate peripheral and central effects. Injection of CP-100,263, the inactive enantiomer of CP-99,994 was used as a control for nonspecific effects of the antagonist. Immunohistochemistry and Western blotting analysis revealed an up-regulation of the NK-1 receptor occurs in the pancreas but not at the spinal cord level. The NK-1 antagonist was able to attenuate the nociceptive behaviors in rats with pancreatitis when applied intraperitoneally with a short duration of effectiveness. Intrathecal application of the antagonist was ineffective. These results suggest the involvement of pancreatic NK-1 receptors in the maintenance of nociception during pancreatic inflammation.

Topics: Acute Disease; Animals; Disease Models, Animal; Male; Neurokinin-1 Receptor Antagonists; Organotin Compounds; Pain Measurement; Pancreatitis; Piperidines; Rats; Rats, Inbred Lew; Receptors, Neurokinin-1