title: P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac.
abstract: Our laboratory has previously demonstrated that peripheral inflammatory pain (PIP), induced by subcutaneous plantar injection of λ-carrageenan, results in increased expression and activity of the ATP-dependent efflux transporter P-glycoprotein (P-gp) that is endogenously expressed at the blood-brain barrier (BBB). The result of increased P-gp functional expression was a significant reduction in CNS uptake of morphine and, subsequently, reduced morphine analgesic efficacy. A major concern in the treatment of acute pain/inflammation is the potential for drug-drug interactions resulting from P-gp induction by therapeutic agents co-administered with opioids. Such effects on P-gp activity can profoundly modulate CNS distribution of opioid analgesics and alter analgesic efficacy. In this study, we examined the ability of diclofenac, a non-steroidal anti-inflammatory drug (NSAID) that is commonly administered in conjunction with the opioids during pain therapy, to alter BBB transport of morphine via P-gp and whether such changes in P-gp morphine transport could alter morphine analgesic efficacy. Administration of diclofenac reduced paw edema and thermal hyperalgesia in rats subjected to PIP, which is consistent with the known mechanism of action of this NSAID. Western blot analysis demonstrated an increase in P-gp expression in rat brain microvessels not only following PIP induction but also after diclofenac treatment alone. Additionally, in situ brain perfusion studies showed that both PIP and diclofenac treatment alone increased P-gp efflux activity resulting in decreased morphine brain uptake. Critically, morphine analgesia was significantly reduced in animals pretreated with diclofenac (3 h), as compared to animals administered diclofenac and morphine concurrently. These novel findings suggest that administration of diclofenac and P-gp substrate opioids during pain pharmacotherapy may result in a clinically significant drug-drug interaction.
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Lucy
authors: L
authors: Sanchez-Covarrubias
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Lauren M
authors: LM
authors: Slosky
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Brandon J
authors: BJ
authors: Thompson
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Yifeng
authors: Y
authors: Zhang
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Mei-Li
authors: ML
authors: Laracuente
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Kristin M
authors: KM
authors: DeMarco
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Patrick T
authors: PT
authors: Ronaldson
authors: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Thomas P
authors: TP
authors: Davis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002351:Carrageenan; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004008:Diclofenac / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006930:Hyperalgesia / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009020:Morphine / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D009020:Morphine; D002351:Carrageenan