Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord

• Published in: Journal of neuroinflammation Vol. 15; no. 1; p. 176
• Main Authors: Zhang, Ting-Ting, Xue, Rui, Fan, Shi-Yong, Fan, Qiong-Yin, An, Lei, Li, Juan, Zhu, Lei, Ran, Yu-Hua, Zhang, Li-Ming, Zhong, Bo-Hua, Li, Yun-Feng, Ye, Cai-Ying, Zhang, You-Zhi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07.06.2018; BioMed Central; BMC
• Subjects: Ammoxetine; Analgesics; Animal models; Animals; Anti-inflammatory drugs; Antidepressants; Astrocytes; Benzodioxoles - chemistry; Benzodioxoles - therapeutic use; c-Jun protein; Calcium-Binding Proteins - metabolism; Causes of; Cell culture; Cell Line, Transformed; Complications and side effects; Cytokines; Diabetes; Diabetes mellitus; Diabetic neuropathic pain; Diabetic neuropathies; Diabetic Neuropathies - chemically induced; Diabetic Neuropathies - complications; Diabetic Neuropathies - drug therapy; Diabetic neuropathy; Disease Models, Animal; Dosage and administration; Dose-Response Relationship, Drug; Drug therapy; Drugs; Duloxetine Hydrochloride - therapeutic use; Experiments; Exploratory Behavior - drug effects; FDA approval; Fibromyalgia; Glia; Hyperalgesia - drug therapy; Hyperalgesia - physiopathology; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Inflammation; Injection; JNK protein; Kinases; Laboratory animals; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Locomotion - drug effects; Locomotor activity; MAP kinase; Microfilament Proteins - metabolism; Microglia; Microglia - drug effects; Mitogen-activated protein kinase; Myelitis - drug therapy; Myelitis - etiology; Myelitis - pathology; NF-κB protein; Norepinephrine; Pain; Pain perception; Propylamines - chemistry; Propylamines - therapeutic use; Proteins; Rats; Rodents; Serotonin; SNRI; Spinal cord; Streptozocin; Streptozocin - toxicity; Transcription factors; Tricyclic antidepressants; China; Beijing China; United States > US; Ammoxetine; Mitogen-activated protein kinase; Cytokines; Diabetic neuropathic pain; SNRI; Glia
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-018-1216-3

Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.