Induction of antinociception and increased met-enkephalin plasma levels by cyclosporine and morphine in rats: implications of the combined use of cyclosporine and morphine and acute posttransplant neuropsychosis.
BACKGROUND
Cyclosporine A (CsA) and morphine have neurotoxic and psychiatric side effects, respectively. Endogenous opiatelike peptides can elicit a number of behavioral responses that mimic the symptoms of psychiatric illness. The purpose of this study was to quantitiate the changes of Met-enkephalin (ME) and beta-endorphin (BE) after administration of CsA and morphine in surgery and to assess the antinociceptive effect.


METHODS
Pain sensitivity, an antinociceptive indicator in rats, was determined with the hotplate test. Plasma ME and BE levels were measured with radioimmunoassays.


RESULTS
In normal unoperated rats, CsA induced a profound analgesic effect concomitant with an increased plasma ME level on day 1. Morphine produced an analgesic effect on days 1 and 2, with decreased ME levels on days 2 and 3. Coadministration of CsA and morphine prolonged the analgesia from days 1 to 4 and increased the plasma ME level on day 1. No change in plasma BE level was found. In surgically operated rats, CsA induced an analgesic effect and higher ME levels than those in unoperated rats. Interestingly, the combined use of CsA and morphine prolonged the analgesia and increased plasma ME levels from days 1 to 4, with no significant change in plasma BE levels.


CONCLUSIONS
Our results showed that CsA can induce antinociception and increase plasma ME levels. This induction can be potentiated by the addition of morphine. Acute neuropsychiatric manifestations in the early posttransplant period might, therefore, be due to induction of ME after coadministration of CsA and morphine.
Lee
Po Chang
PC
Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. pochang@mail.ncku.edu.tw
Tsai
Yu Chuan
YC
Hung
Chung Jye
CJ
Lin
Yih Jyh
YJ
Lei
Huan Yao
HY
Chuang
Jih Ing
JI
Hsu
Kuei Sen
KS
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004744:Enkephalin, Methionine / Q000097:blood* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D010149:Postoperative Pain / Q000188:drug therapy; D011183:Postoperative Complications / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014180:Transplantation / Q000523:psychology; D001615:beta-Endorphin / Q000097:blood / Q000378:metabolism
D000701:Analgesics, Opioid; D007166:Immunosuppressive Agents; D004744:Enkephalin, Methionine; D001615:beta-Endorphin; D009020:Morphine; D016572:Cyclosporine