Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice.
BACKGROUND
We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.


METHODS
C57BL/6 mice received morphine injections thrice daily using increasing doses (5-20 mg∙kg(-1)) for 3 days (sub-acute, n=6) or 14 days (chronic, n=6) and additionally either s-ketamine (5 mg∙kg(-1), n=6) or clonidine (0.1 mg∙kg(-1), n=6). Tail flick test and the assessment of the mechanical withdrawal threshold of the hindpaw was performed during and 4 days after cessation of opioid treatment. Upon completion of the behavioural testing the mRNA-concentration of the NMDA receptor (NMDAR1) and β-arrestin 2 (Arrb2) were measured by PCR.


RESULTS
Chronic opioid treatment resulted in a delay of the tail flick latency with a rapid on- and offset. Simultaneously the mice developed a static mechanical hyperalgesia with a delayed onset that that outlasted the morphine treatment. Sub-acute morphine administration resulted in a decrease of NMDAR1 and Arrb2 whereas during longer opioid treatment the expression NMDAR1 and Arrb2 mRNA increased again to baseline values. Coadministration of s-ketamine or clonidine resulted in a reversal of the mechanical hyperalgesia and inhibited the normalization of NMDAR1 mRNA expression but had no effect on the expression of Arrb2 mRNA.


CONCLUSIONS
In the model of chronic morphine therapy the antinociceptive effects of morphine are represented by the thermal analgesia while the proniceptive effects are represented by the mechanical hyperalgesia. The results indicate that the regulation of the expression of NMDAR1 and Arrb2 may be associated to the development of OIH in mice.


CONCLUSIONS
The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.
Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Henning
H
Ohnesorge
Zhiying
Z
Feng
Karina
K
Zitta
Markus
M
Steinfath
Martin
M
Albrecht
Berthold
B
Bein
D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D019390:Arrestins / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics*; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000009:adverse effects; D010146:Pain / Q000188:drug therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D007649:Ketamine; D009020:Morphine; D003000:Clonidine