title: Co-administration of ultra-low dose naloxone attenuates morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords.
abstract: Although mechanisms underlying ultra-low dose naloxone-induced analgesia have been proposed, possible interactions with glutamatergic transmission and glial cell activation have not been addressed. In the present study, we examined the effect of ultra-low dose naloxone on spinal glutamatergic transmission and glial cell activity in rats chronically infused with morphine. In male Wistar rats, intrathecal morphine infusion (15microg/h) for 5days induced (1) antinociceptive tolerance, (2) downregulation of glutamate transporters (GTs) GLT-1, GLAST, and EAAC1, (3) increasing of NMDA receptor (NMDAR) NR1 subunit expression and phosphorylation, (4) upregulation of protein kinase C gamma (PKCgamma) expression, and (5) glial cell activation. On day 5, morphine challenge (15microg/10microl) caused a significant increase in the concentration of the excitatory amino acids (EAAs) aspartate and glutamate in the spinal CSF dialysates of morphine-tolerant rats. Intrathecal co-infusion of ultra-low dose naloxone (15pg/h) with morphine attenuated tolerance development, reversed GTs expression, inhibited the NMDAR NR1 subunit expression and phosphorylation, and PKCgamma expression, inhibited glial cell activation, and suppressed the morphine-evoked EAAs release. These effects may result in preservation of the antinociceptive effect of acute morphine challenge in chronic morphine-infused rats. Ultra-low dose naloxone infusion alone did not produce an antinociceptive effect. These findings demonstrated that attenuation of glutamatergic transmission and neuroinflammation by ultra-low dose naloxone co-infusion preserves the lasting antinociceptive effect of morphine in rats chronically infused with morphine.
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shinn-Long
authors.initials: SL
authors.lastname: Lin
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Shen
authors.forename: Fu-Huang
authors.initials: FH
authors.lastname: Lin
authors.forename: Jhi-Joung
authors.initials: JJ
authors.lastname: Wang
authors.forename: Shih-Tai
authors.initials: ST
authors.lastname: Hsin
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000134:cerebrospinal fluid; D004347:Drug Interactions; D004361:Drug Tolerance; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D027322:Amino Acid Transport System X-AG; D000700:Analgesics; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C493398:Slc1a1 protein, rat; D001224:Aspartic Acid; D009270:Naloxone; D018698:Glutamic Acid; D009020:Morphine; C087857:protein kinase C gamma; D011493:Protein Kinase C