Abstract
The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. An incision was made on the plantar aspect of the hind paw. Mechanical hypersensitivity was measured by determining the withdrawal threshold to von Frey filaments applied to the paw. Drugs were administered intrathecally 24 h after paw incision. Microdialysis studies of the dorsal horn of the lumbar spinal cord were also performed to measure 5-HT and NA levels after systemic injection of milnacipran. Milnacipran (1–30 μg) produced dose-dependent antihypersensitivity effects. The effect lasted 6 h after the 30-μg injection. Doses of 30 μg or less produced no abnormal behavior. The peak antihypersensitivity effect of 10 μg of milnacipran was blocked by intrathecal pretreatment with antagonists of the α2-adrenoceptor (idazoxan; 30 μg) or 5-HT receptors (methysergide; 30 μg). Intrathecal pretreatment with 30 μg of naloxone, a μ-opioid receptor antagonist, did not reverse the effect of milnacipran. Isobolographic analysis indicated antinociceptive synergism between milnacipran and morphine. Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine-mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity.
Footnotes
This work was supported by the Ministry of Education, Science, Sports and Culture of Japan [Grants-in-Aid for Scientific Research 12671451, 20791065, 20390412].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.168336.
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ABBREVIATIONS:
- NA
- noradrenaline
- 5-HT
- serotonin
- TCA
- tricyclic antidepressant
- SNRI
- serotonin and noradrenaline reuptake inhibitor
- NMDA
- N-methyl-d-aspartate
- %MPE
- percentage maximum possible effect
- AUC
- area under the time course curve
- ANOVA
- analysis of variance
- i.d.
- inner diameter
- o.d.
- outer diameter.
- Received March 19, 2010.
- Accepted June 16, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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