Impaired noradrenaline homeostasis in rats with painful diabetic neuropathy as a target of duloxetine analgesia

Molecular Pain

Fusao Kato¹  Kazunori Utsunomiya³  Ayako M Watabe¹  Yukari Takahashi²  Jun Kinoshita³ 

[1] Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;Department of Neuroscience, Jikei University School of Medicine, Minato, Tokyo 105-8461, Japan;Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato, Tokyo 105-8461, Japan

关键词: Norepinephrine transporter;    Dopamine-beta-hydroxylase;    Spinal cord;    Duloxetine;    DSP-4;    Noradrenaline;    Diabetes mellitus;    Streptozotocin;    Pain;   

Others  :  862105
DOI  :  10.1186/1744-8069-9-59

 received in 2013-09-19, accepted in 2013-11-22,  发布年份 2013

【 摘 要 】

Background

Painful diabetic neuropathy (PDN) is a serious complication of diabetes mellitus that affects a large number of patients in many countries. The molecular mechanisms underlying the exaggerated nociception in PDN have not been established. Recently, duloxetine (DLX), a serotonin and noradrenaline re-uptake inhibitor, has been recommended as one of the first-line treatments of PDN in the United States Food and Drug Administration, the European Medicines Agency and the Japanese Guideline for the Pharmacologic Management of Neuropathic pain. Because selective serotonin re-uptake inhibitors show limited analgesic effects in PDN, we examined whether the potent analgesic effect of DLX contributes toward improving the pathologically aberrant noradrenaline homeostasis in diabetic models.

Results

In streptozotocin (STZ) (50 mg/kg, i.v.)-induced diabetic rats that exhibited robust mechanical allodynia and thermal hyperalgesia, DLX (10 mg/kg, i.p.) significantly and markedly increased the nociceptive threshold. The analgesic effect of DLX was nullified by the prior administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg, i.p.), which drastically eliminated dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the lumbar spinal dorsal horn and significantly reduced the noradrenaline content in the lumbar spinal cord. The treatment with DSP-4 alone markedly lowered the nociceptive threshold in vehicle-treated non-diabetic rats; however, this pro-nociceptive effect was occluded in STZ-treated diabetic rats. Furthermore, STZ-treated rats exhibited a higher amount of dopamine-beta-hydroxylase- and norepinephrine transporter-immunopositive fibers in the dorsal horn and noradrenaline content in the spinal cord compared to vehicle-treated rats.

Conclusions

Impaired noradrenaline-mediated regulation of the spinal nociceptive network might underlie exaggerated nociception in PDN. DLX might exert its analgesic effect by selective enhancement of noradrenergic signals, thus counteracting this situation.

【 授权许可】

   
2013 Kinoshita et al.; licensee BioMed Central Ltd.

【 图 表 】

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