title: Mechanisms of morphine-venlafaxine interactions in diabetic neuropathic pain model.
abstract: BACKGROUND
  we investigated the possible mechanisms involved in the interactions of venlafaxine (VFX), a selective serotonin and noradrenaline reuptake inhibitor, and morphine (MRF), an opioid receptor agonist, after acute and chronic VFX treatment in diabetic neuropathic pain model (DNPM).
  
  
  METHODS
  The studies were performed on male rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall-Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of streptozotocin. In order to investigate the mechanism of interaction, animals were also pretreated with naloxone (NLX), a nonselective opioid antagonist, yohimbine (YOH), a nonselective α2-adrenergic antagonist, and p-chloroamphetamine (PCA), a neurotoxin that destroys serotonergic neurons. The μ-opioid receptors' density was determined with the use of radioligand binding assay.
  
  
  RESULTS
  VFX potentiated antinociceptive action of MRF after acute administration of VFX and this effect was decreased by pretreatment of NLX, YOH and PCA. On the contrary, VFX administered for 21 days prior to MRF significantly decreased the analgesic action of MRF; this effect was augmented only after YOH pretreatment. Also, 21-days administration of VFX caused decreasing tendency in the number of μ-opioid receptors in the brain stem.
  
  
  CONCLUSIONS
  The results of our study show that single administration of VFX potentiates antinociceptive action of morphine in DNPM. This effect is probably mediated by both, noradrenergic and serotonergic systems. On the other hand, 21-days administration of VFX significantly decreases analgesic action of MRF. Moreover, there is a possibility that VFX acts as an antagonist of N-methyl-d-aspartate receptors.
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT) Laboratory, Medical University of Warsaw, Warszawa, Poland. Electronic address: kcegielska@wum.edu.pl.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Cegielska-Perun
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT) Laboratory, Medical University of Warsaw, Warszawa, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Tatarkiewicz
authors.affiliation: Department of Pharmacobiology, Jagiellonian University, Medical College, Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Jagiellonian University, Medical College, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dybała
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT) Laboratory, Medical University of Warsaw, Warszawa, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bujalska-Zadrożny
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000818:Animals; D001933:Brain Stem / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004357:Drug Synergism; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy*; D017288:Pain Threshold; D010812:Physical Stimulation; D051381:Rats; D017450:Receptors, Opioid, mu / Q000187:drug effects; D018490:Serotonin Agents / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D015016:Yohimbine / Q000627:therapeutic use; D010133:p-Chloroamphetamine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D018490:Serotonin Agents; D015016:Yohimbine; D010133:p-Chloroamphetamine; D009020:Morphine; D000069470:Venlafaxine Hydrochloride
keywords: Diabetes; Interactions; Morphine; Venlafaxine; Yohimbine