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Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice.

Ohnesorge H, Feng Z, Zitta K, Steinfath M, Albrecht M, Bein B - PLoS ONE (2013)

Bottom Line: 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.The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

ABSTRACT

Background: We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.

Material and 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.

Conclusion: 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.

Perspective: The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

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Related in: MedlinePlus

Protocol of drug administration.D: day. Numbers (0.1, 5, 10, 20) display the dose of drugs in mg·kg-1, 0 represents saline. Application was performed subcutaneously in a volume of 200-300µl thrice daily. N=6 animals per group.
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pone-0079567-g001: Protocol of drug administration.D: day. Numbers (0.1, 5, 10, 20) display the dose of drugs in mg·kg-1, 0 represents saline. Application was performed subcutaneously in a volume of 200-300µl thrice daily. N=6 animals per group.

Mentions: The dosing scheme used for morphine administration is shown in Figure 1. Additionally to the treatment groups P (placebo), AM (sub-acute morphine) and CM (chronic morphine) four groups received morphine and either clonidine or s-ketamine. Group LM (clonidine/chronic morphine) received 0.1 mg/kg clonidine trice daily on D1-D14, group KM (ketamine/chronic morphine) 5mg/kg s-ketamine trice daily on D1-D14. Group L (clonidine/placebo) and group K (ketamine/placebo) received the same doses of clonidine and ketamine but without morphine on D1-D14. Six animals were assigned to each group. Four days after the last injection, mice were decapitated, brains were removed from the skull and immediately flash-frozen in liquid nitrogen and stored at -80 °C until RNA extraction.


Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice.

Ohnesorge H, Feng Z, Zitta K, Steinfath M, Albrecht M, Bein B - PLoS ONE (2013)

Protocol of drug administration.D: day. Numbers (0.1, 5, 10, 20) display the dose of drugs in mg·kg-1, 0 represents saline. Application was performed subcutaneously in a volume of 200-300µl thrice daily. N=6 animals per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815130&req=5

pone-0079567-g001: Protocol of drug administration.D: day. Numbers (0.1, 5, 10, 20) display the dose of drugs in mg·kg-1, 0 represents saline. Application was performed subcutaneously in a volume of 200-300µl thrice daily. N=6 animals per group.
Mentions: The dosing scheme used for morphine administration is shown in Figure 1. Additionally to the treatment groups P (placebo), AM (sub-acute morphine) and CM (chronic morphine) four groups received morphine and either clonidine or s-ketamine. Group LM (clonidine/chronic morphine) received 0.1 mg/kg clonidine trice daily on D1-D14, group KM (ketamine/chronic morphine) 5mg/kg s-ketamine trice daily on D1-D14. Group L (clonidine/placebo) and group K (ketamine/placebo) received the same doses of clonidine and ketamine but without morphine on D1-D14. Six animals were assigned to each group. Four days after the last injection, mice were decapitated, brains were removed from the skull and immediately flash-frozen in liquid nitrogen and stored at -80 °C until RNA extraction.

Bottom Line: 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.The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

ABSTRACT

Background: We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.

Material and 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.

Conclusion: 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.

Perspective: The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

Show MeSH
Related in: MedlinePlus