title: Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia.
abstract: Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here, we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force, and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression, reward, and pain modulation.
authors.affiliation: Department of Psychology, The Center for Neuroscience, University of Colorado at Boulder, Campus Box 345, Boulder, CO 80309-0345, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Alexis L
authors.initials: AL
authors.lastname: Northcutt
authors.forename: Lindsey W
authors.initials: LW
authors.lastname: Chao
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kearney
authors.forename: Yingning
authors.initials: Y
authors.lastname: Zhang
authors.forename: Debra L
authors.initials: DL
authors.lastname: Berkelhammer
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Robert R
authors.initials: RR
authors.lastname: Rozeske
authors.forename: Sondra T
authors.initials: ST
authors.lastname: Bland
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Todd T
authors.initials: TT
authors.lastname: Gleeson
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000698:Analgesia; D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects
chemical_list: D009294:Narcotics; D012333:RNA, Messenger; D009020:Morphine; D051545:Cyclooxygenase 1; D008911:Minocycline