title: The involvement of midbrain astrocyte in the development of morphine tolerance.
abstract: OBJECTIVE
  Systemic administration of opiate analgesics such as morphine remains the most effective treatment for alleviating severe pain across a range of conditions including acute pain. However, chronic or repeated administration of opiate analgesics results in the development of analgesic tolerance. Glial cells such as microglia and astrocytes are known to release various inflammatory cytokines and neurotrophic factors leading to regulation of neuronal function. Recently, glial cells were reported to play important roles in the development of analgesic tolerance to morphine. Here, we focused on the involvement of midbrain glial cells, particularly astrocytes, in the development of analgesic tolerance to morphine.
  
  
  METHODS
  Mice were treated with morphine (10mg/kg, s.c.) or vehicle once a day for 5 days. Pentoxifylline (an inhibitor of glial activation; 20mg/kg, i.p. or 50 and 100 μg/mouse, i.c.v.) was administered 30 min before morphine treatment. Flavopiridol (a cyclin-dependent kinase inhibitor; 5 nmol/mouse, i.c.v.) was administered 10 min before and 10h after morphine treatment. The analgesic effect of morphine was measured using the tail flick method.
  
  
  RESULTS
  The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine for 5 days in mice. On days 1 and 3 after repeated morphine treatment, astrocyte marker glial fibrillary acidic protein expression levels were significantly increased, as determined by western blot analyses. These phenomena were significantly inhibited following pre-treatment with pentoxifylline or flavopiridol.
  
  
  CONCLUSIONS
  We demonstrated that midbrain astrocytes play an important role in the development of analgesic tolerance to morphine.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-0045, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D004361:Drug Tolerance; D005419:Flavonoids / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D005419:Flavonoids; D005904:Glial Fibrillary Acidic Protein; D010880:Piperidines; C077990:alvocidib; D009020:Morphine; D010431:Pentoxifylline
keywords: Analgesic tolerance; Astrocyte; Midbrain; Morphine