title: Morphine glucuronidation increases its analgesic effect in guinea pigs.
abstract: OBJECTIVE
  Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different roles, interindividual variability and co-administration of drugs that interfere with metabolism may affect analgesia. The aim of the study was to investigate the repercussions of administration of an inducer (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and an inhibitor (ranitidine) of glucuronidation in morphine metabolism and consequent analgesia, using the Guinea pig as a suitable model.
  
  
  METHODS
  Thirty male Dunkin-Hartley guinea pigs were divided in six groups: control, morphine, ranitidine, ranitidine+morphine, TCDD and TCDD+morphine. After previous exposure to TCDD and ranitidine, morphine effect was assessed by an increasing temperature hotplate (35-52.5°C), during 60min after morphine administration. Then, blood was collected and plasma morphine and metabolites were quantified.
  
  
  RESULTS
  Animals treated with TCDD presented faster analgesic effect and 75% reached the cut-off temperature of 52.5°C, comparing with only 25% in morphine group. Animals treated with ranitidine presented a significantly lower analgesic effect, compared with morphine group (p<0.05). Moreover, significant differences between groups were found in M3G levels and M3G/morphine ratio (p<0.001 and p<0.0001), with TCDD animals presenting the highest values for M3G, M6G, M3G/morphine and M6G/morphine, and the lowest value for morphine. The opposite was observed in the animals treated with ranitidine.
  
  
  CONCLUSIONS
  Our results indicate that modulation of morphine metabolism may result in variations in metabolite concentrations, leading to different analgesic responses to morphine, in an animal model that may be used to improve morphine effect in clinical practice.
authors: REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; Molecular Oncology GRP and Virology LB, Portuguese Institute of Oncology-Porto, Porto, Portugal; IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences - North, (ISCS-N), CESPU, CRL, Gandra Portugal. Electronic address: anacorreiadeoliveira@gmail.com.
authors: Ana
authors: A
authors: Oliveira
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal; IBMC - Institute of Molecular and Cell Biology, University of Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors: Dora
authors: D
authors: Pinho
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal; IBMC - Institute of Molecular and Cell Biology, University of Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors: António
authors: A
authors: Albino-Teixeira
authors: Molecular Oncology GRP and Virology LB, Portuguese Institute of Oncology-Porto, Porto, Portugal; ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal; Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal; LPCC, Portuguese League Against Cancer, Regional Centre of the North, Porto, Portugal.
authors: Rui
authors: R
authors: Medeiros
authors: REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences - North, (ISCS-N), CESPU, CRL, Gandra Portugal; Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal.
authors: Ricardo Jorge
authors: RJ
authors: Dinis-Oliveira
authors: REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. Electronic address: felixdc@ff.up.pt.
authors: Félix
authors: F
authors: Carvalho
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D008297:Male; D009020:Morphine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000494:pharmacology; D011899:Ranitidine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D000072317:Polychlorinated Dibenzodioxins; C035349:morphine-6-glucuronide; D009020:Morphine; D011899:Ranitidine; C018108:morphine-3-glucuronide
keywords: Morphine; Morphine metabolism; Morphine-3-glucuronide; Morphine-6-glucuronide; Pain assessment