title: Amitriptyline preserves morphine's antinociceptive effect by regulating the glutamate transporter GLAST and GLT-1 trafficking and excitatory amino acids concentration in morphine-tolerant rats.
abstract: The present study was undertaken to examine the effect of amitriptyline on the antinociceptive effect of morphine and its underlying mechanisms in regulating glutamate transporters trafficking in morphine-tolerant rats. Long-term morphine infusion induced antinociceptive tolerance and down-regulation of glutamate transporters (GTs), GLAST, GLT-1, and EAAC1, expression in the rat spinal cord dorsal horn. Acute amitriptyline treatment potentiated morphine's antinociceptive effect, with a 5.3-fold leftward shift of morphine's dose-response curve in morphine-tolerant rats, and this was associated with GLAST and GLT-1 trafficking onto the cell surface. Similar to our previous studies, morphine challenge (10 microg/10 microl, i.t.) significant by increased the excitatory amino acids (EAAs) aspartate and glutamate level in the CSF dialysates of morphine-tolerant rats. Acute amitriptyline treatment not only suppressed this morphine-evoked EAA release, but further reduced the EAA concentration than baseline level. Furthermore, long-term morphine infusion up-regulated PKA and PKC protein expression in the spinal cord dorsal horn, while amitriptyline inhibited the increase in expression of phospho-PKA, PKCalpha, PKCbetaII, and PKCgamma. In morphine-tolerant rats, acute treatment with PKA inhibitor H89 and PKC inhibitor Gö6805 attenuated morphine tolerance and the morphine-induced CSF glutamate and aspartate elevation, and induced trafficking of GLAST and GLT-1 from cytosol onto the cell surface. These results show that acute amitriptyline treatment preserved morphine's antinociceptive effect in morphine-tolerant rats; the mechanisms may be involved in inhibition of phospho-PKA and PKC expression, and thus inducing the GLAST and GLT-1 trafficking onto glial cell surface which enhances the EAA uptake from the synaptic cleft and reduces EAA concentration in the spinal CSF.
authors.affiliation: Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan Department of Anesthesiology, Tri-service General Hospital and National Defense Medical Center, 325 Chenggung Road, Section 2, Neihu 114, Taipei, Taiwan Department of Medical Research and Anesthesiology, Chi-Mei Medical Center, Yung-Kang City, Tainan, Taiwan Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yueh-Hua
authors.initials: YH
authors.lastname: Tai
authors.forename: Yu-Hsueh
authors.initials: YH
authors.lastname: Wang
authors.forename: Ru-Yin
authors.initials: RY
authors.lastname: Tsai
authors.forename: Jhi-Joung
authors.initials: JJ
authors.lastname: Wang
authors.forename: Pao-Luh
authors.initials: PL
authors.lastname: Tao
authors.forename: Tso-Mei
authors.initials: TM
authors.lastname: Liu
authors.forename: Ya Chin
authors.initials: YC
authors.lastname: Wang
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000639:Amitriptyline / Q000008:administration & dosage*; D000700:Analgesics / Q000008:administration & dosage; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004361:Drug Tolerance / Q000502:physiology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D004338:Drug Combinations; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; C493398:Slc1a1 protein, rat; C493392:Slc1a3 protein, rat; D000639:Amitriptyline; D009020:Morphine