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

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 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.