Effect of the deficiency of spinal PSD-95/SAP90 on the minimum alveolar anesthetic concentration of isoflurane in rats.
BACKGROUND
Spinal N-methyl-D-aspartate (NMDA) receptor activation has been demonstrated to play an important role in the processing of spinal nociceptive information and in the determination of the minimum alveolar anesthetic concentration (MAC) of inhalational anesthetics. Postsynaptic density-95 (PSD-95)/synapse-associated protein-90 (SAP90), a molecular scaffolding protein that binds and clusters the NMDA receptor perferentially at synapses, was implicated in NMDA-induced thermal hyperalgesia. The current study investigated the possible involvement of PSD-95/SAP9O in determining MAC for isoflurane anesthesia.


METHODS
Sprague-Dawley rats were pretreated intrathecally with PSD-95/SAP90 antisense oligodeoxyribonucleotide (ODN), sense ODN, missense ODN, or saline every 24 h for 4 days. After initial baseline determination of the MAC, NMDA or saline was injected intrathecally. Ten minutes later, MAC measurement was repeated. The rats also were evaluated for the presence of locomotor dysfunction by intrathecal administration of NMDA or saline in the saline- and ODN-treated rats.


RESULTS
In the groups treated with antisense ODNs, but not in those treated with sense or missense ODNs, there was a significant decrease in isoflurane MAC that was not accompanied by marked changes in either blood pressure or heart rate. In the saline-treated group, intrathecal NMDA caused an increase in isoflurane MAC. In contrast, in the antisense ODN-treated group, intrathecal NMDA did not produce a significant change in isoflurane MAC. An NMDA-induced increase in blood pressure but not heart rate was found in both saline- and antisense ODN-treated groups. Locomotor activity was not changed in any of the treated animals.


CONCLUSIONS
The results indicate not only a significant decrease in MAC for isoflurane but also an attenuation in the NMDA-induced increase in isoflurane MAC in the PSD-95/SAP90 antisense-treated animals, which suggests that PSD-95/SAP90 may mediate the role of the NMDA receptor in determining the MAC of inhalational anesthetics.
Tao
Y X
YX
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Unviersity School of Medicine, Baltimore, Maryland 21287-4965, USA.
Johns
R A
RA
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D007278:Injections, Spinal; D047908:Intracellular Signaling Peptides and Proteins; D007530:Isoflurane / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism*
D018685:Anesthetics, Inhalation; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020320:Oligoribonucleotides, Antisense; C033652:postsynaptic density proteins; D016202:N-Methylaspartate; D007530:Isoflurane