Dynorphinergic mechanism mediating endomorphin-2-induced antianalgesia in the mouse spinal cord.
We have previously demonstrated that both endomorphin-1 (EM-1) and endomorphin-2 (EM-2) at high doses (1.75-35 nmol) given intrathecally (i.t.) or intracerebroventricularly produce antinociception by stimulation of mu-opioid receptors. Now, we report that EM-2 at small doses (0.05-1.75 nmol), which injected alone did not produce antinociception, produces anti-analgesia against opioid agonist-induced antinociception. The tail-flick (TF) response was used to test the antinociception in male CD-1 mice. Intrathecal pretreatment with EM-2 (0.02-1.75 nmol) 45 min before i.t. morphine (3.0 nmol) injection dose dependently attenuated morphine-induced TF inhibition. On the other hand, a similar dose of EM-1 (1.64 nmol) failed to produce any antianalgesic effect. The EM-2 (1.75 nmol)-produced anti-analgesia against morphine-induced TF inhibition was blocked by i.t. pretreatment with the mu-opioid antagonist naloxone or 3-methoxynaltrexone, but not delta-opioid receptor antagonist naltrindole, kappa-opioid receptor antagonist nor-binaltorphimine, or N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. The EM-2-induced antianalgesic effect against morphine-induced TF inhibition was blocked by i.t. pretreatment with antiserum against dynorphin A(1-17), but not beta-endorphin, [Met]-enkephalin, [Leu]-enkephalin, or cholecystokinin antiserum (200 microg each). The i.t. EM-2 pretreatment also attenuated the TF inhibition induced by other mu-opioid agonists, [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin, EM-1 and EM-2, delta-opioid agonist deltorphin II, and kappa-opioid agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488H). It is concluded that EM-2 at subanalgesic doses presumably stimulates a subtype of mu-opioid receptor and subsequently induces the release of dynorphin A(1-17) to produce antianalgesic effects against mu-, delta-, or kappa-agonists-induced antinociception. The EM-2-induced antianalgesia is not mediated by the release of [Met]-enkephalin, [Leu]-enkephalin, beta-endorphin, or cholecystokinin, nor does it involve kappa- or delta-opioid or NMDA receptors in the spinal cord.
Wu
Hsiang-En
HE
Department of Anesthesiology, Medical College of Wisconsin, Medical Education Building, Room M4308, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
Sun
Han-Sen
HS
Darpolar
Moses
M
Leitermann
Randy J
RJ
Kampine
John P
JP
Tseng
Leon F
LF
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects*
C107547:3-methoxynaltrexone; D000701:Analgesics, Opioid; D019138:Antibodies, Blocking; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; D009270:Naloxone; C105294:endomorphin 2; D009271:Naltrexone; D016291:Dizocilpine Maleate; D004399:Dynorphins; D009020:Morphine