| Abstract No.: | C-D3154 |
| Country: | Brazil |
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| Title: | SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITOR REDUCES THE PHOSPHORYLATION OF CYCLIC AMP-RESPONSIVE ELEMENT-BINDING PROTEIN IN THE MICE SPINAL CORD DORSAL HORN FOLLOWING PERIPHERAL NERVE INJURY. |
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| Authors/Affiliations: | 1 Ricardo Kusuda*; 1 Paula Santos; 1 Sonia Zanon; 1 Guilherme Lucas;
1 University of São Paulo School of Medicine, Department of Physiology, Ribeirao Preto, Brazil
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| Content: | Objective: Chronic administration of imipramine, a serotonin and norepinephrine reuptake inhibitor (SNRI) is considered an effective drug to attenuate mechanical and thermal-induced neuropathic pain hyperalgesia. However, the cellular mechanism underlying this effect remains unknown. In addition, increased phosphorylation of the transcription factor cyclic AMP-responsive element-binding protein (CREB) is also associated to the development of thermal hyperalgesia induced by peripheral nerve injury. Here we investigate the effect of chronic administration of imipramine on CREB phosphorylation in the spinal cord dorsal horn following peripheral nerve lesion.
Materials and Methods: Adult Balb/C male mice weighting 20-25g were used. Unilateral nerve lesion was induced by partial ligation of sciatic nerve. Imipramine (30mg/kg), or saline (10µL/g) were daily injected for 21 days after 7 days post-nerve injury. The development of tactile mechanical hypersensitivity was monitored by Von Frey filaments once a week, 24 hours after the last drug injection. PhosphoCREB immunoreactivity was investigated in the lumbar (L4-L6) spinal cord dorsal horn 7 and 28 days after nerve injury, and in lesioned animals treated with imipramine for 21 days.
Results: Tactile-induced neuropathic pain hypersensitivity was observed from 7 to 28 days after nerve ligation (p < 0.05, non-parametric Mann-Whitney test). In addition, CREB phosphorylation increased in the superficial laminae of the spinal cord ipsilateral to the lesion after 7 and 28 days post-injury. However, daily administration of imipramine progressively reduced mechanical hypersensitivity from the first week of treatment, and completely reversed tactile stimulus-induced hypersensitivity after 21 days of therapy (p < 0.05, non-parametric Mann-Whitney test). Following chronic SNRI administration, the increased phosphorylation of CREB protein was also reversed in the spinal cord dorsal horn. Surprisingly, the antinociceptive effect of imipramine was still observed 3 weeks after cessation of treatment.
Conclusion: these results indicate that chronic administration of imipramine induces plastic changes in the sensory system that may take time to develop and mature, which might explain in part why the clinical analgesic effect of SNRI develops with a delay after the beginning of the treatment. Our data also provide evidence that prolonged SNRI treatment may induce antinociception in neuropathic pain conditions by reducing CREB-mediated transcription.
Approved by the local Animal Care and Ethics Committee (# 213/2007)
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