Central versus peripheral site of action of the tachykinin NK1-antagonist RP 67580 in inhibiting chemonociception.
1. Many studies indicate an involvement of substance P in the transmission of nociceptive stimuli, without, however, presenting any conclusive evidence as to its exact site and mode of action. The present experiments tested the involvement of substance P in the mediation of chemical nociception using the non-peptidic specific tachykinin NK1-receptor antagonist, RP 67580 (2-[1-imino-2-(2-methoxyphenyl-ethyl]-7,7diphenyl-4-perhydroiso indolone (3aR, 7aR)). 2. Mean arterial pressure (MAP) and intragastric pressure (IGP) were measured in anaesthetized rats. The reflex changes of these parameters in response to i.p. or s.c. injections of hydrochloric acid or capsaicin were taken to indicate nociception. 3. Intravenous administration of RP 67580 up to 5 mg kg-1 had little influence on the reflex changes in MAP or IGP in response to hydrochloric acid or capsaicin. In contrast, the sensitization of rats to i.p. capsaicin by preinjection of prostaglandin E2 was significantly reduced by 1 mg kg-1 RP 67580. 4. Intrathecal injection of 5 micrograms RP 67580 inhibited the reflex changes of MAP and IGP in response to i.p. or s.c. capsaicin whereas the inactive enantiomer RP 68651 was ineffective. 5. The results indicate that spinal NK1-receptors are involved in the acute transmission of chemically induced pain, while such receptors in the periphery take part in the sensitization by prostaglandin E2. The rather minor ability of i.v. RP 67580 to inhibit the acute nociceptive reflex is attributed to an insufficient penetration of the blood-brain-barrier.
Holzer-Petsche
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Department of Experimental and Clinical Pharmacology, Karl-Franzens-University, Graz, Austria.
Rordorf-Nikolić
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T
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D006851:Hydrochloric Acid / Q000008:administration & dosage / Q000633:toxicity; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D054833:Isoindoles; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013237:Stereoisomerism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000502:physiology*
D000700:Analgesics; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D006851:Hydrochloric Acid; D002211:Capsaicin