Antinociception produced by oral, subcutaneous or intrathecal administration of SC-39566, an opioid dipeptide arylalkylamide, in the rodent.
This study characterized the prototypic "minimum structure" enkephalin SC-39566 [2,6-dimethyl-L-tyrosinyl-D-alanine-(3-phenyl-1-propyl)-amide hydrochloride]. SC-39566 bound with highest affinity to mu opioid receptors (Ki, 0.13 nM), as well as to delta (Ki, 4.0 nM) opioid receptors in the rat brain, and with much lower affinity to kappa opioid receptors (Ki, 83.8 nM) in the guinea pig brain. In the mouse, SC-39566 inhibited phenylbenzoquinone-induced writhing and increased tail-flick and hot-plate latencies in a dose-dependent manner after either s.c. or p.o. (i.g.; intragastrical) administration. This antinociception was antagonized by the opioid antagonist naloxone, but not by alpha adrenergic, serotonergic, histaminergic, muscarinic cholinergic or dopaminergic receptor antagonists. In the rat, SC-39566 dose-dependently inhibited acetic-acid-induced writhing after s.c. or i.g. administration and increased response latencies in the tail-flick and hot-plate test after s.c. or intrathecal (i.t.) administration. The increase in tail-flick latency produced by s.c. SC-39566 in the rat was antagonized by s.c. naloxone with an apparent pA2 value of 7.9. Pretreatment with naltrindole, a delta opioid receptor antagonist, increased the ED50 of SC-39566 by only 1.7-fold. In addition, the increase in tail-flick latency produced by i.t. SC-39566 was not antagonized by i.t. administration of naltrindole or nor-binaltorphimine, a kappa receptor antagonist. These data suggest that the antinociceptive activity of SC-39566 is mediated predominantly by mu opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Hammond
D L
DL
Department of Anesthesia and Critical Care, University of Chicago, Illinois.
Stapelfeld
A
A
Drower
E J
EJ
Savage
M A
MA
Tam
L
L
Mazur
R H
RH
D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D013997:Time Factors
D000700:Analgesics; D004151:Dipeptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C072400:2,6-dimethyltyrosyl-N-(3-phenylpropyl)alaninamide