Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils.
Intravenous administration of the NK1 receptor antagonist L-733,060 to gerbils 3 h before intraplantar injection of formalin caused a dose-dependent and complete inhibition of the late, but not early, phase nociceptive response (paw licking). The ID50 for L-733,060 (0.17 mg/kg) revealed a greater than 50-fold separation in potency over its less active enantiomer L-733,061 (ID50 > or = 10 mg/kg). In contrast, the non-brain penetrant quaternary ketone NK1 receptor antagonist, L-743,310 (3 mg/kg), did not attenuate the response to formalin, indicating that the antinociceptive effect of blockade of NK1 receptors by L-733,060 in this assay is centrally-mediated. These findings add to the preclinical evidence that NK1 receptor antagonists may be of therapeutic use as centrally-acting analgesics.
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow,Essex CM20 2QR, UK.
Nadia M J
NMJ
Rupniak
Emma
E
Carlson
Susan
S
Boyce
Janine K
JK
Webb
Raymond G
RG
Hill
D000818:Animals; D005260:Female; D005528:Foot; D005557:Formaldehyde / Q000494:pharmacology*; D005849:Gerbillinae; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors
D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; C068032:GR 73632; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; D005557:Formaldehyde; D013373:Substance P