Neuroprotective effects of remifentanil against transient focal cerebral ischemia in rats.
BACKGROUND
Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined.


METHODS
Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes' middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 μg/kg/min) was given alone or combined with naltrindole (δ-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (μ-opioid receptor antagonist; 1 mg/kg), or 5'-guanidinonaltrindole (κ-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-α (TNF-α) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion.


RESULTS
Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm(3) vs. 108.9±24.8 mm(3)), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) or 5'-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-α, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment.


CONCLUSIONS
Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain.
Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea.
Seongtae
S
Jeong
Seok Jai
SJ
Kim
Cheolwon
C
Jeong
Seongheon
S
Lee
Hyejin
H
Jeong
Jongun
J
Lee
Kyung Yeon
KY
Yoo
D018686:Anesthetics, Intravenous / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D002245:Carbon Dioxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009422:Nervous System Diseases / Q000209:etiology / Q000523:psychology; D018696:Neuroprotective Agents; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077208:Remifentanil; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018686:Anesthetics, Intravenous; D015850:Interleukin-6; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; D002245:Carbon Dioxide; D009271:Naltrexone; D020928:Mitogen-Activated Protein Kinases; C055382:naltrindole; D000077208:Remifentanil