title: Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice.
abstract: We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wawrzczak-Bargiela
authors.forename: Maria
authors.initials: M
authors.lastname: Osikowicz
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology*; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010431:Pentoxifylline / Q000008:administration & dosage / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D012584:Sciatic Nerve / Q000293:injuries; D020426:Sciatic Neuropathy / Q000209:etiology / Q000503:physiopathology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D039481:CD11b Antigen; D039521:CD11c Antigen; D005904:Glial Fibrillary Acidic Protein; D010975:Platelet Aggregation Inhibitors; D009020:Morphine; D008911:Minocycline; D010431:Pentoxifylline