Long-Term Antidepressant Treatment Inhibits Neuropathic Pain-Induced CREB and PLC gamma-1 Phosphorylation in the Mouse Spinal Cord Dorsal Horn

Autor(es)

Kusuda, Ricardo ^[1] ; Ravanelli, Maria I. ^[1] ; Cadetti, Flaviane ^{[1, 2]} ; Franciosi, Adriano ^[1] ; Previdelli, Karina ^{[1, 2]} ; Zanon, Sonia ^[1] ; Lucas, Guilherme ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Pain Neurobiol Lab, Dept Physiol, Ribeirao Preto Sch Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Neurosci & Behav, Div Neurol, Ribeirao Preto Sch Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF PAIN; v. 14, n. 10, p. 1162-1172, OCT 2013.
• Citações Web of Science: 5

Resumo

The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate-responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase gamma-1 (PLC gamma-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLC gamma-1 but not extracellular signal-regulated kinase (ERK42), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury-induced CREB and PLCy-1 phosphorylation but had no effect on ERK1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLC gamma-1/CREB-signaling pathway. Perspective: This article demonstrates that long-term treatment with imipramine reverses some of the marked effects induced by peripheral nerve injury in the spinal dorsal horn that contribute to long-term maintenance of sensory disorder, providing a new view to the mechanisms of action of these drugs. (C) 2013 by the American Pain Society (AU)

• Processo FAPESP: 06/00479-0 - Ação das neurotrofinas na atividade antinociceptiva do sistema monoaminérgico: integrando neurogênese e mecanismos de dor neuropática
• Beneficiário: Guilherme de Araújo Lucas
• Modalidade de apoio: Auxílio à Pesquisa - Regular