Nonopioidergic mechanism mediating morphine-induced antianalgesia in the mouse spinal cord.
Intrathecal (i.t.) pretreatment with a low dose (0.3 nmol) of morphine causes an attenuation of i.t. morphine-produced analgesia; the phenomenon has been defined as morphine-induced antianalgesia. The opioid-produced analgesia was measured with the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with low dose (0.3 nmol) of morphine time dependently attenuated i.t. morphine-produced (3.0 nmol) TF inhibition and reached a maximal effect at 45 min. Intrathecal pretreatment with morphine (0.009-0.3 nmol) for 45 min also dose dependently attenuated morphine-produced TF inhibition. The i.t. morphine-induced antianalgesia was dose dependently blocked by the nonselective mu-opioid receptor antagonist (-)-naloxone and by its nonopioid enantiomer (+)-naloxone, but not by endomorphin-2-sensitive mu-opioid receptor antagonist 3-methoxynaltrexone. Blockade of delta-opioid receptors, kappa-opioid receptors, and N-methyl-D-aspartate (NMDA) receptors by i.t. pretreatment with naltrindole, nor-binaltorphimine, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), respectively, did not affect the i.t. morphine-induced antianalgesia. Intrathecal pretreatment with antiserum against dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, beta-endorphin, cholecystokinin, or substance P also did not affect the i.t. morphine-induced antianalgesia. The i.t. morphine pretreatment also attenuated the TF inhibition produced by opioid muagonist [D-Ala2, N-Me-Phe4,Gly-ol5]-enkephalin, delta-agonist deltorphin II, and kappa-agonist U50,488H. It is concluded that low doses (0.009-0.3 nmol) of morphine given i.t. activate an antianalgesic system to attenuate opioid mu-, delta-, and kappa-agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid mu-, delta-, or kappa-receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, beta-endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Hsiang-En
HE
Wu
Jonathan
J
Thompson
Han-Sen
HS
Sun
Randy J
RJ
Leitermann
James M
JM
Fujimoto
Leon F
LF
Tseng
D000698:Analgesia; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004361:Drug Tolerance; D004399:Dynorphins / Q000276:immunology / Q000378:metabolism; D004745:Enkephalins / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000627:therapeutic use; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects*; D013373:Substance P / Q000276:immunology / Q000378:metabolism; D001615:beta-Endorphin / Q000276:immunology / Q000378:metabolism
C107547:3-methoxynaltrexone; D004745:Enkephalins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013373:Substance P; D009270:Naloxone; C051844:norbinaltorphimine; C105294:endomorphin 2; D009271:Naltrexone; D001615:beta-Endorphin; D016291:Dizocilpine Maleate; D004399:Dynorphins; D009020:Morphine; C055382:naltrindole