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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

Effect of s-ketamine alone and in combination with chronic morphine administration on the mechanical threshold (A) and the tail flick latency (B).Mechanical threshold and tail flick latency were evaluated daily before injection (D-4-D0), during injection (D1-D14) and after injection (D15-D18). The grey shaded surface represents 4 days (D15-D18) after injection. The results are presented as %MPE ± SEM (n = 6). P: placebo group; CM: chronic morphine administration group; K: s-ketamine administration group; KM: coadministration of morphine with s-ketamine group. *P<0.05; **P<0.01 compared with baseline; whereas #P<0.01 compared with group CM.
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pone-0079567-g004: Effect of s-ketamine alone and in combination with chronic morphine administration on the mechanical threshold (A) and the tail flick latency (B).Mechanical threshold and tail flick latency were evaluated daily before injection (D-4-D0), during injection (D1-D14) and after injection (D15-D18). The grey shaded surface represents 4 days (D15-D18) after injection. The results are presented as %MPE ± SEM (n = 6). P: placebo group; CM: chronic morphine administration group; K: s-ketamine administration group; KM: coadministration of morphine with s-ketamine group. *P<0.05; **P<0.01 compared with baseline; whereas #P<0.01 compared with group CM.

Mentions: No significant differences in baseline values of each group (D-4 to D0) or among the groups were found for both the mechanical thresholds and the tail flick latencies (P>0.05, data not shown). Short term morphine administration (group AM) resulted in no changes in mechanical hyperalgesia but in a delay of the tail flick latency during opioid-administration. Chronic opioid therapy (group CM) resulted in a decrease of the mechanical threshold that lasted at least 4 days longer than the morphine-administration, while the delay of the tail flick latency lasted not longer than the morphine treatment (Figure 2). Clonidine in a dose of 0.1 mg∙kg-1 (group L) did affect neither the mechanical threshold nor the tail flick latency. Coadministration of morphine and clonidine (group LM) resulted in an increase of the mechanical threshold that returned to baseline value immediately after end of treatment and a pronounced delay of the tail flick latency compared to group CM (Figure 3). Administration of s-ketamine in a dose of 5mg∙kg-1 (group K) resulted also in unchanged mechanical thresholds and tail flick latencies compared to group P. Compared to group CM, coadministration of s-ketamine and morphine (group KM) resulted in an increase of the mechanical threshold that returned to baseline value after end of treatment and a pronounced delay of the tail flick latency (Figure 4).


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)

Effect of s-ketamine alone and in combination with chronic morphine administration on the mechanical threshold (A) and the tail flick latency (B).Mechanical threshold and tail flick latency were evaluated daily before injection (D-4-D0), during injection (D1-D14) and after injection (D15-D18). The grey shaded surface represents 4 days (D15-D18) after injection. The results are presented as %MPE ± SEM (n = 6). P: placebo group; CM: chronic morphine administration group; K: s-ketamine administration group; KM: coadministration of morphine with s-ketamine group. *P<0.05; **P<0.01 compared with baseline; whereas #P<0.01 compared with group CM.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3815130&req=5

pone-0079567-g004: Effect of s-ketamine alone and in combination with chronic morphine administration on the mechanical threshold (A) and the tail flick latency (B).Mechanical threshold and tail flick latency were evaluated daily before injection (D-4-D0), during injection (D1-D14) and after injection (D15-D18). The grey shaded surface represents 4 days (D15-D18) after injection. The results are presented as %MPE ± SEM (n = 6). P: placebo group; CM: chronic morphine administration group; K: s-ketamine administration group; KM: coadministration of morphine with s-ketamine group. *P<0.05; **P<0.01 compared with baseline; whereas #P<0.01 compared with group CM.
Mentions: No significant differences in baseline values of each group (D-4 to D0) or among the groups were found for both the mechanical thresholds and the tail flick latencies (P>0.05, data not shown). Short term morphine administration (group AM) resulted in no changes in mechanical hyperalgesia but in a delay of the tail flick latency during opioid-administration. Chronic opioid therapy (group CM) resulted in a decrease of the mechanical threshold that lasted at least 4 days longer than the morphine-administration, while the delay of the tail flick latency lasted not longer than the morphine treatment (Figure 2). Clonidine in a dose of 0.1 mg∙kg-1 (group L) did affect neither the mechanical threshold nor the tail flick latency. Coadministration of morphine and clonidine (group LM) resulted in an increase of the mechanical threshold that returned to baseline value immediately after end of treatment and a pronounced delay of the tail flick latency compared to group CM (Figure 3). Administration of s-ketamine in a dose of 5mg∙kg-1 (group K) resulted also in unchanged mechanical thresholds and tail flick latencies compared to group P. Compared to group CM, coadministration of s-ketamine and morphine (group KM) resulted in an increase of the mechanical threshold that returned to baseline value after end of treatment and a pronounced delay of the tail flick latency (Figure 4).

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