Abstract
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 μ-opioid receptor antagonist (-)-naloxone and by its nonopioid enantiomer (+)-naloxone, but not by endomorphin-2-sensitive μ-opioid receptor antagonist 3-methoxynaltrexone. Blockade of δ-opioid receptors, κ-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, β-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 μagonist [d-Ala2, N-Me-Phe4,Gly-ol5]-enkephalin, δ-agonist deltorphin II, and κ-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 μ-, δ-, and κ-agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid μ-, δ-, or κ-receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, β-endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.
Footnotes
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This work was supported by Grants DA 03811 and DA12588 from the National Institutes of Health, National Institute on Drug Abuse (to L.F.T.).
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DOI: 10.1124/jpet.104.065334.
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ABBREVIATIONS: TF, tail-flick; %MPE, percent maximum possible effect; NTI, naltrindole; nor-BNI, nor-binaltorphimine; NMDA, N-methyl-d-aspartate; MK-801, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; DAMGO, [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin; CCK, cholecystokinin; ANOVA, analysis of variance; CI, confidence interval; U50,488H, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate.
- Received January 8, 2004.
- Accepted March 3, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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