title: cAMP and protein kinase A contribute to the downregulation of spinal glutamate transporters after chronic morphine.
abstract: Our previous study has shown that spinal glutamate transporters (GTs) are downregulated following chronic morphine administration; however, how spinal GTs are regulated in this process remains unclear. Here we show that the downregulation of spinal GTs (EAAC1 and GLT-1) induced by a 6-day intrathecal morphine (10 microg, twice daily) treatment regimen was prevented by co-administration of morphine with 2',5'-dideoxyadenosine (ddA, 1 microg, a broad adenylyl cyclase inhibitor) or H89 (10 microg, a selective protein kinase A inhibitor). When co-administered with morphine, ddA or H89 also effectively attenuated the development of morphine tolerance in the same rats, while ddA or H89 alone did not affect the baseline nociceptive response. These results indicate that the downregulation of spinal GTs following chronic morphine is at least in part mediated through the intracellular cyclic AMP and protein kinase A pathway, suggesting that this cellular mechanism of GT regulation may be contributory to the development of morphine tolerance in rats.
authors.affiliation: Pain Research Group, MGH Pain Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Grewo
authors.initials: G
authors.lastname: Lim
authors.forename: Shuxing
authors.initials: S
authors.lastname: Wang
authors.forename: Jianren
authors.initials: J
authors.lastname: Mao
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016048:Dideoxyadenosine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004347:Drug Interactions; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism; D013997:Time Factors
chemical_list: C101692:5-methyl-1-nicotinoyl-2-pyrazoline; D027322:Amino Acid Transport System X-AG; D000701:Analgesics, Opioid; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D007546:Isoquinolines; D009539:Nicotinic Acids; D047428:Protein Kinase Inhibitors; C493398:Slc1a1 protein, rat; D013449:Sulfonamides; D027981:Symporters; D005576:Colforsin; D016048:Dideoxyadenosine; D009020:Morphine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide