title: Imipramine ameliorates pain-related negative emotion via induction of brain-derived neurotrophic factor.
abstract: Depression-like behavior is often complicated by chronic pain. Antidepressants including imipramine (IMI) are widely used to treat chronic pain, but the mechanisms are not fully understood. Brain-derived neurotrophic factor (BDNF) is a neuromodulator that reduces depression by regulating synaptic transmission. We aimed to characterize the antidepressant effects of IMI without analgesia based on BDNF (trkB)-mediated signaling and gene expression in chronic pain. A chronic constriction injury (CCI) model was constructed in Sprague-Dawley (SD) rats. IMI (5 mg/kg, i.p.) was administered from day 10 after CCI. The pain response was assessed using the paw withdrawal latency (PWL) and depression was judged from the immobility time in a forced swim test. Anti-BDNF antibody, K252a, or 5,7-dihydroxytryptamine (5,7-DHT) were used to examine the antidepressant effects of imipramine. Changes in pERK1/2 (immunohistochemistry), 5-HT and BDNF (ELISA), and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC), rostral ventromedial medulla (RVM), and spinal cord. After CCI, rats showed decreased PWL and increased immobility time. A low dose of IMI reduced the immobility time without having analgesic effects. This antidepressant effect was reversed by anti-BDNF antibody, K252a, and 5,7-DHT. IMI reduced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA, and these changes were reversed by 5,7-DHT. These results show that IMI reduces pain-related negative emotion without influencing pain and that this effect is diminished by denervation of 5-HT neurons and by anti-BDNF treatment. IMI also normalizes derangement of ERK/CREB coupling, which leads to induction of BDNF. This suggests a possible interaction between 5-HT and BDNF.
authors.affiliation: Division of Neurosciences, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Yasuda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamagata
authors.forename: Yasutake
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Hiromi
authors.initials: H
authors.lastname: Suenaga
authors.forename: Kozo
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Masako
authors.initials: M
authors.lastname: Nakano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okuyama
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Shoei
authors.initials: S
authors.lastname: Furukawa
authors.forename: Toshizo
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D059350:Chronic Pain / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D003251:Constriction, Pathologic; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004644:Emotions / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D048049:Extracellular Signal-Regulated MAP Kinases; D007099:Imipramine