Differential mechanisms mediating descending pain controls for antinociception induced by supraspinally administered endomorphin-1 and endomorphin-2 in the mouse.
We have previously demonstrated that both endomorphin-1 and endomorphin-2 produce their antinociception by the stimulation of mu-opioid receptors. However, the antinociception induced by endomorphin-2 contains an additional component, which is mediated by the release of dynorphin A (1-17) acting on kappa-opioid receptors. These studies were done to determine whether the antinociception induced by endomorphin-1 and endomorphin-2 given supraspinally was mediated by the activation of different descending pain control pathways in the mouse. Specific receptor antagonists or antisera against endogenous opioid peptides were injected intrathecally to block the receptors or bind the released endogenous opioid peptides, and endomorphin-1 or endomorphin-2 was then administered i.c.v. to activate the descending pain control systems to produce antinociception. The tail-flick response was used as antinociceptive test. The blockade of the alpha(2)-adrenoceptors and 5-hydroxytryptamine receptors in the spinal cord by i.t. injection of yohimbine and methysergide, respectively, inhibited the antinociception induced by i.c.v.-administered endomorphin-1 and endomorphin-2. However, the antinociception induced by endomorphin-2 was inhibited by i.t. pretreatment with delta(2)-opioid receptor antagonist naltriben or kappa-opioid receptor antagonist nor-binaltorphimine, but not by the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH(2) or the delta(1)-opioid receptor antagonist 7-benzylidene naltrexamine. Intrathecal pretreatment with antiserum against Met-enkephalin attenuated the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1. Furthermore, i.t. pretreatment with antiserum against dynorphin A (1-17) also inhibited the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1. Intrathecal pretreatment with antiserum against Leu-enkephalin or beta-endorphin did not inhibit i.c.v.-administered endomorphin-1- or endomorphin-2-induced antinociception. The results indicate that, like other opioid micro-receptor agonists, morphine, and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin, endomorphin-1 and endomorphin-2 given i.c.v. produce antinociception by activating spinipetal noradrenergic and serotonergic pathways for producing antinociception. However, the antinociception induced by endomorphin-2 given i.c.v. also contains other components, which are mediated by the release of Met-enkephalin and dynorphin A (1-17) acting on opioid delta(2)- and kappa-receptors, respectively, in the spinal cord.
Ohsawa
M
M
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Mizoguchi
H
H
Narita
M
M
Chu
M
M
Nagase
H
H
Tseng
L F
LF
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D007106:Immune Sera; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology / Q000502:physiology*; D018847:Opioid Peptides / Q000276:immunology / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D007106:Immune Sera; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D018341:Receptors, Adrenergic, alpha-2; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012702:Serotonin Antagonists; C105293:endomorphin 1; C105294:endomorphin 2