PMID- 25283187 OWN - NLM STAT- MEDLINE DCOM- 20151117 LR - 20230525 IS - 1573-6830 (Electronic) IS - 0272-4340 (Linking) VI - 35 IP - 2 DP - 2015 Mar TI - Neurotropin((R)) ameliorates chronic pain via induction of brain-derived neurotrophic factor. PG - 231-41 LID - 10.1007/s10571-014-0118-x [doi] AB - Neurotropin (NTP)((R)), a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, is used clinically for the treatment of neuropathic pain. Moreover, NTP may activate the descending pain inhibitory system. Depression-like behavior is often complicated by chronic pain. However, little is known about NTP-mediated prevention of mood disorders in chronic pain and its molecular mechanisms. We aimed to investigate the effects of NTP on brain-derived neurotrophic factor (BDNF)-mediated signaling and gene expression in chronic pain. In addition, these effects of NTP were compared with pregabalin which is an anticonvulsant, anxiolytic analgesic used to treat neuropathic pain and fibromyalgia. A chronic constriction injury model was established in Sprague-Dawley rats. The pain response was assessed using a paw withdrawal latency (PWL) test and depression was assessed by the immobility time in a forced swim test (FST). NTP was orally administered in two doses of 50 NU (Neurotropin Unit) and 100 NU/kg for 7 days from day 7 after injury. To measure the analgesic and anti-depressant effects of NTP, either K252a (a tyrosine kinase inhibitor), or 5,7-dihydroxy tryptamine (5,7-DHT, a selective toxin for 5-HTergic neurons) was administered by intracerebroventricular injection. Changes in pERK1/2 and pCREB (immunohistochemistry), 5-HT, and BDNF protein level (ELISA) and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC) and in the rostral ventromedial medulla (RVM) 14 days after injury. After injury, the rats showed a decrease in PWL associated with the increase in time of immobility in FST. In this injury model, NTP blocked both the decrease in PWL and the increase in the FST, while pregabalin (10 mg/kg, po.) did not affect the increase in the FST. These effects of NTP were reversed by K252a, and 5,7-DHT. The analgesic effects of pregabalin were not reversed by K252a. NTP normalized the injury-induced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA in the ACC and in the RVM, and these changes were reversed by 5,7-DHT. In contrast, pregabalin did not affect either pCREB or BDNF levels in the chronic pain model. NTP ameliorated chronic pain and pain-related depression by normalizing the induction of BDNF associated with the 5-HTergic system. Pregabalin showed the analgesic effects but had no effects on either depression or the BDNF pathway. These results suggest that NTP may represent an additional drug strategy for chronic pain associated with depression. FAU - Ishikawa, Toshizo AU - Ishikawa T AD - Division of Neurosciences, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan, medlibn@yamaguchi-u.ac.jp. FAU - Yasuda, Seiko AU - Yasuda S FAU - Minoda, Seiji AU - Minoda S FAU - Ibuki, Takae AU - Ibuki T FAU - Fukuhara, Kayoko AU - Fukuhara K FAU - Iwanaga, Yasutake AU - Iwanaga Y FAU - Ariyoshi, Toru AU - Ariyoshi T FAU - Sasaki, Hironori AU - Sasaki H LA - eng PT - Journal Article DEP - 20141005 PL - United States TA - Cell Mol Neurobiol JT - Cellular and molecular neurobiology JID - 8200709 RN - 0 (Analgesics) RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Polysaccharides) RN - 0 (Protein Kinase Inhibitors) RN - 0 (RNA, Messenger) RN - 57657-35-9 (neurotropin) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Analgesics/pharmacology MH - Animals MH - Antidepressive Agents/pharmacology/therapeutic use MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Chronic Pain/*drug therapy/genetics/pathology MH - Constriction, Pathologic MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Gyrus Cinguli/drug effects/metabolism MH - Male MH - Phosphorylation/drug effects MH - Polysaccharides/pharmacology/*therapeutic use MH - Protein Kinase Inhibitors/pharmacology MH - RNA, Messenger/genetics/metabolism MH - Rabbits MH - Rats, Sprague-Dawley MH - Serotonergic Neurons/drug effects/metabolism MH - Swimming EDAT- 2014/10/07 06:00 MHDA- 2015/11/18 06:00 CRDT- 2014/10/07 06:00 PHST- 2014/08/28 00:00 [received] PHST- 2014/09/23 00:00 [accepted] PHST- 2014/10/07 06:00 [entrez] PHST- 2014/10/07 06:00 [pubmed] PHST- 2015/11/18 06:00 [medline] AID - 10.1007/s10571-014-0118-x [doi] PST - ppublish SO - Cell Mol Neurobiol. 2015 Mar;35(2):231-41. doi: 10.1007/s10571-014-0118-x. Epub 2014 Oct 5.