Antiallodynic and antihyperalgesic effect of milnacipran in mice with spinal nerve ligation.
BACKGROUND
The antidepressant, milnacipran, has been reported to have antinociceptive, antiallodynic, and antihyperalgesic effects. In this study, we examined the mechanisms of the antiallodynic and antihyperalgesic effects of milnacipran in a model of neuropathic pain induced by spinal nerve ligation in mice.


METHODS
The fifth left lumbar nerve of male C57BL6 mice was tightly ligated. Withdrawal threshold to tactile stimulation and withdrawal latency to heat stimulation in the injured or contralateral paw was tested by using von Frey filaments and radiant heat, respectively.


RESULTS
Milnacipran was administered either orally (7.5-120 mg/kg), intrathecally, intracerebroventricularly, or locally (210 ng-21 microg). Both systemic, intrathecal and intracerebroventricular milnacipran increased withdrawal threshold and withdrawal latency in nerve-ligated mice whereas local injection had no effect. Depletion of spinal serotonergic or noradrenergic neurons was achieved by use of the specific neurotoxins, 6-hydroxydopamine or 5,7-dihydroxytryptamine, applied intrathecally 3 days before evaluation of the analgesic effect of milnacipran. Spinal serotonergic and noradrenergic denervation attenuated the effect of milnacipran in sham-operated mice. In nerve-ligated mice, however, the effect of milnacipran was lost after noradrenergic denervation but not after serotonergic denervation.


CONCLUSIONS
We concluded that the antiallodynic and antihyperalgesic effects of milnacipran on neuropathic pain induced by spinal nerve ligation are principally mediated through action at supraspinal and spinal sites via activation of the spinal noradrenergic system.
Suzuki
Takahiro
T
Department of Anesthesiology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, Japan 565-0871. tsuzuki@anes.med.osaka-u.ac.jp
Ueta
Kazuyoshi
K
Tamagaki
Shinji
S
Mashimo
Takashi
T
D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000078764:Milnacipran; D009443:Neuritis / Q000188:drug therapy* / Q000209:etiology; D013116:Spinal Cord / Q000503:physiopathology*
D000700:Analgesics; D000928:Antidepressive Agents; D003521:Cyclopropanes; D000078764:Milnacipran