title: Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance.
abstract: Compelling evidence has suggested that spinal glial cells were activated by chronic morphine treatment and involved in the development of morphine tolerance. However, the mechanisms of glial activation were still largely unknown in morphine tolerance. In present study, we investigated the role of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal cord in the development of chronic morphine antinociceptive tolerance. We found that intrathecal administration of morphine (15 microg) daily for 7 consecutive days significantly induced an increase in number of phospho-p38 (p-p38) immunoreactive cells in the spinal cord compared with chronic saline or acute morphine treated rats. Double immunofluorescence staining revealed that p-p38 immunoreactivity was exclusively restricted in the activated spinal microglia, not in astrocytes or neurons. Repeated intrathecal administration of 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) (10 microg or 2 microg), a specific p38 inhibitor, 30 min before each morphine injection for 7 consecutive days significantly attenuated tolerance to morphine analgesia assessed by tail flick test. However, a single intrathecal administration of SB203580 (10 microg) did not antagonize the established tolerance to morphine analgesia. Taken together, these findings suggested that p38 MAPK activation in the spinal microglia was involved in the development of morphine antinociceptive tolerance. Inhibition of p38 MAPK by SB203580 in the spinal cord attenuated but not reversed the tolerance to morphine analgesia. The present study provides the first evidence that p38 activation in spinal microglia played an important role in the development of tolerance to morphine analgesia.
authors.affiliation: Department of Physiology, Zhongshan Medical College, Sun Yat-Sen University, No. 74, Zhongshan Rd. 2, Guangzhou 510080, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Zhi
authors.forename: Rui-Xian
authors.initials: RX
authors.lastname: Guo
authors.forename: Jian-Qiang
authors.initials: JQ
authors.lastname: Feng
authors.forename: Pei-Xi
authors.initials: PX
authors.lastname: Chen
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D017628:Microglia / Q000502:physiology*; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D009021:Morphine Dependence / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007093:Imidazoles; D011725:Pyridines; D009020:Morphine; D048051:p38 Mitogen-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase; C093642:SB 203580