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NEUROPHARMACOLOGY

Nonopioidergic Mechanism Mediating Morphine-Induced Antianalgesia in the Mouse Spinal Cord

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin

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 -opioid receptors, -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, -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, -agonist deltorphin II, and -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-, -, and -agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid µ-, -, or -receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, -endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.

Address correspondence to: Dr. Leon F. Tseng, Department of Anesthesiology, Medical College of Wisconsin, Medical Education Bldg., Rm M4308, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ltseng{at}post.its.mcw.edu

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