Antiinflammatory and analgesic activity of a non-peptide substance P receptor antagonist.
CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.
Nagahisa
A
A
Department of Medicinal Biology, Central Research Division, Pfizer Inc., Aichi, Japan.
Kanai
Y
Y
Suga
O
O
Taniguchi
K
K
Tsuchiya
M
M
Lowe
J A
JA
Hess
H J
HJ
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010972:Platelet Activating Factor / Q000494:pharmacology; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013189:SRS-A / Q000494:pharmacology; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D015320:Tachykinins / Q000494:pharmacology; D014513:Ureter / Q000187:drug effects
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D010972:Platelet Activating Factor; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D013189:SRS-A; D015320:Tachykinins; D006632:Histamine; D002211:Capsaicin; D001920:Bradykinin; C066892:CP 96345