Inhibition of dynorphin-converting enzymes prolongs the antinociceptive effect of intrathecally administered dynorphin in the mouse formalin test.
The effects of peptidase inhibitors on the antinociceptive induced by intrathecally (i.t.) administered by dynorphin A and dynorphin B in the mouse formalin test were examined. When administered i.t. 5 min before the injection of 0.5% formalin solution into the dorsal surface of a hindpaw, dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) produced a dose-dependent and significant reduction of the paw-licking response. Dynorphin A (2 nmol) and dynorphin B (8 nmol)-induced antinociception disappeared completely within 90 min and 60 min, respectively. p-Hydroxymercuribenzoate, a cysteine proteinase inhibitor, and phosphoramidon, and endopeptidase 24.11 inhibitor simultaneously administered with dynorphin A or dynorphin B. Significantly prolonged antinociception induced by both dynorphins. However, captopril, and angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine proteinase inhibitor phenylmethanesulfonyl fluoride, were active. Dynorphin converting enzyme(s) transform dynorphin-related peptides to [Leu5]enkephalin and [Leu5]enkephalin-Arg6. Neither [Leu5]enkephalin nor [Leu5]enkephalin-Arg6, even at high dose (10 nmol), produced any antinociceptive effect. However, [Leu5[enkephalin-Arg6, but not [Leu5]enkephalin, produced a significant antinociceptive effect when co-administered with phosphoramidon. Therefore, the prolongation of the antinociception induced by both dynorphins in the presence of phosphoramidon, may be due to inhibition of [Leu5]enkephalin-Arg6 degradation. The present results indicate that dynorphin-converting enzyme(s) may be important enzyme(s) responsible for terminating dynorphin-A- and dynorphin-B-induced antinociception at the spinal cord level in mice.
Tan-No
K
K
Department of Pharmacology, Tohoku College of Pharmacy, Sendai, Japan.
Taira
A
A
Sakurada
T
T
Inoue
M
M
Sakurada
S
S
Tadano
T
T
Sato
T
T
Sakurada
C
C
Nylander
I
I
Silberring
J
J
Terenius
L
L
Kisara
K
K
D000698:Analgesia; D000818:Animals; D003546:Cysteine Endopeptidases / Q000494:pharmacology*; D004399:Dynorphins / Q000008:administration & dosage*; D004723:Endorphins / Q000008:administration & dosage*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D010147:Pain Measurement
D004723:Endorphins; D004399:Dynorphins; C036200:rimorphin; D003546:Cysteine Endopeptidases; C063078:dynorphin converting enzyme