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The interaction of intrathecal neostigmine and N-cyclohexyladenosine on anti-allodynic effects in rats with a nerve ligation injury.

Choi DK, Choi SS, Hwang JH - Korean J Anesthesiol (2010)

Bottom Line: Neostigmine, CHA, and the neostigmine-CHA combination dose-dependently produced anti-allodynia effects.Side effects such as sedation and motor weakness were similar in the three groups.Intrathecal co-administration of neostigmine and CHA showed a synergistic anti-allodynia effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

ABSTRACT

Background: Nerve ligation injury in rats produces a pain syndrome that includes mechanical allodynia. Intrathecal administration of cholinesterase inhibitors or adenosine receptor agonists have anti-allodynic effects in this model. Therefore, we tested the interaction between intrathecal neostigmine and N(6)-cyclohexyladenosine (CHA) in a rat behavioral model of neuropathic pain.

Methods: Male Sprague-Dawley rats were prepared with tight ligation of the spinal nerves for producing allodynia and with a lumbar intrathecal catheter for drug administration. Allodynia thresholds for hindpaw withdrawal against mechanical stimuli were assessed and converted to percent maximal possible effect. Neostigmine (0.3-10 microg) and CHA (0.03-3 microg) were administered to obtain the dose-response curves and the 50% effective dose (ED(50)). Equal fractions (1/2, 1/4 and 1/8 ED(50)s) of the two drugs were administered to establish the ED(50) of neostigmine-CHA combination. Side effects were also assessed. The drug interaction was evaluated by isobolographic and fractional analyses.

Results: Neostigmine, CHA, and the neostigmine-CHA combination dose-dependently produced anti-allodynia effects. Side effects such as sedation and motor weakness were similar in the three groups. In the isobolographic analysis, the experimental ED(50) for the combination of neostigmine-CHA lay far below and to the left of the theoretical additive line. Fractional analysis indicated that the total combination fraction of the two drugs was 0.39.

Conclusions: Intrathecal co-administration of neostigmine and CHA showed a synergistic anti-allodynia effect.

No MeSH data available.


Related in: MedlinePlus

Isobologram for the interaction between intrathecal neostigmine and N6-cyclohexyladenosine. Horizontal and vertical bars indicate SEM. The diagonal line connecting two 50% effective dose (ED50) points is the theoretical additive line. The ED50 point A is calculated from the ED50 values and 95% confidence intervals of each drug. The experimental ED50 point B lies far below the line of additivity, indicating significant synergism. CHA: N6-cyclohexyladenosine, Neo: neostigmine. *P < 0.05 compared with theoretical ED50 point A.
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Figure 2: Isobologram for the interaction between intrathecal neostigmine and N6-cyclohexyladenosine. Horizontal and vertical bars indicate SEM. The diagonal line connecting two 50% effective dose (ED50) points is the theoretical additive line. The ED50 point A is calculated from the ED50 values and 95% confidence intervals of each drug. The experimental ED50 point B lies far below the line of additivity, indicating significant synergism. CHA: N6-cyclohexyladenosine, Neo: neostigmine. *P < 0.05 compared with theoretical ED50 point A.

Mentions: The ED50 values and slopes of neostigmine, CHA, and their combination are described in Table 1. The dose-response curve of the combination group was shifted to the left and steeper compared drug alone (Fig. 1). Isobolographic analysis indicated a synergistic interaction between neostigmine and CHA (Fig. 2). The experimentally determined mixture ED50 (± SEM) was 0.07 µg (±0.016) for neostigmine and 0.02 µg (±0.004) for CHA. The theoretical additive ED50 was calculated to be 0.18 µg (±0.04) for neostigmine and 0.05 µg (±0.01) for CHA. The experimental value of neostigmine-CHA combination was significantly less than the calculated additive value (P < 0.05). The total fraction for the neostigmine-CHA combination was 0.39, indicating a synergistic interaction (Table 2).


The interaction of intrathecal neostigmine and N-cyclohexyladenosine on anti-allodynic effects in rats with a nerve ligation injury.

Choi DK, Choi SS, Hwang JH - Korean J Anesthesiol (2010)

Isobologram for the interaction between intrathecal neostigmine and N6-cyclohexyladenosine. Horizontal and vertical bars indicate SEM. The diagonal line connecting two 50% effective dose (ED50) points is the theoretical additive line. The ED50 point A is calculated from the ED50 values and 95% confidence intervals of each drug. The experimental ED50 point B lies far below the line of additivity, indicating significant synergism. CHA: N6-cyclohexyladenosine, Neo: neostigmine. *P < 0.05 compared with theoretical ED50 point A.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908226&req=5

Figure 2: Isobologram for the interaction between intrathecal neostigmine and N6-cyclohexyladenosine. Horizontal and vertical bars indicate SEM. The diagonal line connecting two 50% effective dose (ED50) points is the theoretical additive line. The ED50 point A is calculated from the ED50 values and 95% confidence intervals of each drug. The experimental ED50 point B lies far below the line of additivity, indicating significant synergism. CHA: N6-cyclohexyladenosine, Neo: neostigmine. *P < 0.05 compared with theoretical ED50 point A.
Mentions: The ED50 values and slopes of neostigmine, CHA, and their combination are described in Table 1. The dose-response curve of the combination group was shifted to the left and steeper compared drug alone (Fig. 1). Isobolographic analysis indicated a synergistic interaction between neostigmine and CHA (Fig. 2). The experimentally determined mixture ED50 (± SEM) was 0.07 µg (±0.016) for neostigmine and 0.02 µg (±0.004) for CHA. The theoretical additive ED50 was calculated to be 0.18 µg (±0.04) for neostigmine and 0.05 µg (±0.01) for CHA. The experimental value of neostigmine-CHA combination was significantly less than the calculated additive value (P < 0.05). The total fraction for the neostigmine-CHA combination was 0.39, indicating a synergistic interaction (Table 2).

Bottom Line: Neostigmine, CHA, and the neostigmine-CHA combination dose-dependently produced anti-allodynia effects.Side effects such as sedation and motor weakness were similar in the three groups.Intrathecal co-administration of neostigmine and CHA showed a synergistic anti-allodynia effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

ABSTRACT

Background: Nerve ligation injury in rats produces a pain syndrome that includes mechanical allodynia. Intrathecal administration of cholinesterase inhibitors or adenosine receptor agonists have anti-allodynic effects in this model. Therefore, we tested the interaction between intrathecal neostigmine and N(6)-cyclohexyladenosine (CHA) in a rat behavioral model of neuropathic pain.

Methods: Male Sprague-Dawley rats were prepared with tight ligation of the spinal nerves for producing allodynia and with a lumbar intrathecal catheter for drug administration. Allodynia thresholds for hindpaw withdrawal against mechanical stimuli were assessed and converted to percent maximal possible effect. Neostigmine (0.3-10 microg) and CHA (0.03-3 microg) were administered to obtain the dose-response curves and the 50% effective dose (ED(50)). Equal fractions (1/2, 1/4 and 1/8 ED(50)s) of the two drugs were administered to establish the ED(50) of neostigmine-CHA combination. Side effects were also assessed. The drug interaction was evaluated by isobolographic and fractional analyses.

Results: Neostigmine, CHA, and the neostigmine-CHA combination dose-dependently produced anti-allodynia effects. Side effects such as sedation and motor weakness were similar in the three groups. In the isobolographic analysis, the experimental ED(50) for the combination of neostigmine-CHA lay far below and to the left of the theoretical additive line. Fractional analysis indicated that the total combination fraction of the two drugs was 0.39.

Conclusions: Intrathecal co-administration of neostigmine and CHA showed a synergistic anti-allodynia effect.

No MeSH data available.


Related in: MedlinePlus