Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse.
Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.
Sakurada
S
S
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Sendai 981-8558, Japan. s-sakura@tohoku-pharm.ac.jp
Hayashi
T
T
Yuhki
M
M
Orito
T
T
Zadina
J E
JE
Kastin
A J
AJ
Fujimura
T
T
Murayama
K
K
Sakurada
C
C
Sakurada
T
T
Narita
M
M
Suzuki
T
T
Tan-no
K
K
Tseng
L F
LF
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000276:immunology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000276:immunology; D004744:Enkephalin, Methionine / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010446:Peptide Fragments / Q000276:immunology; D013997:Time Factors
D000700:Analgesics; D001597:Benzylidene Compounds; D007106:Immune Sera; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; C092588:dynorphin B (1-13); C105293:endomorphin 1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C068868:naltrindole benzofuran; C077358:7-benzylidenenaltrexone; D009270:Naloxone; C051844:norbinaltorphimine; C105294:endomorphin 2; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D009271:Naltrexone; D004399:Dynorphins; C034643:naloxonazine