Differential effects of N-peptidyl-O-acyl hydroxylamines on dynorphin-induced antinociception in the mouse capsaicin test.
In the capsaicin test, intrathecal (i.t.) dynorphins are antinociceptive. Cysteine protease inhibitors such as p-hydroxymercuribenzoate (PHMB) given i.t. augment and prolong their activity. The effect of two novel cysteine protease inhibitors, N-peptidyl-O-acyl hydroxylamines, on the antinociception induced by i.t. administered dynorphin A or dynorphin B has been investigated. When administered i.t. 5 min before the injection of capsaicin (800 ng) into the plantar surface of the hindpaw, dynorphin A (62.5-1000 pmol) or dynorphin B (0.5-4 nmol) produced a dose-dependent and significant antinociceptive effect. The effect of dynorphin A (1 nmol) and dynorphin B (4 nmol) disappeared completely within 180 and 60 min, respectively. PHMB (2 nmol) and Boc-Tyr-Gly-NHO-Bz (BYG-Bz) (2 nmol) co-administered with dynorphin A or dynorphin B significantly prolonged antinociception induced by both. On the other hand, Z-Phe-Phe-NHO-Bz (ZFF-Bz) (1 and 2 nmol) only prolonged antinociception induced by dynorphin A. The results suggest that Z-Phe-Phe-NHO-Bz is an inhibitor of cysteine proteases preferring cleavage of dynorphin A, with less specificity towards dynorphin B in the mouse spinal cord.
Tan-No
Koichi
K
Department of Pharmacology, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan. koichi@tohoku-pharm.ac.jp
Taira
Aki
A
Nakagawasai
Osamu
O
Niijima
Fukie
F
Demuth
Hans-Ulrich
HU
Silberring
Jerzy
J
Terenius
Lars
L
Tadano
Takeshi
T
D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D002211:Capsaicin / Q000378:metabolism*; D004399:Dynorphins / Q000378:metabolism*; D004723:Endorphins / Q000378:metabolism*; D006801:Humans; D006898:Hydroxylamines / Q000378:metabolism*; D006902:Hydroxymercuribenzoates / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D010147:Pain Measurement; D011480:Protease Inhibitors / Q000378:metabolism
D000700:Analgesics; D004723:Endorphins; D006898:Hydroxylamines; D006902:Hydroxymercuribenzoates; D011480:Protease Inhibitors; C030601:4-hydroxymercuribenzoate; D004399:Dynorphins; C036200:rimorphin; D002211:Capsaicin