Impaired rate-dependent depression (RDD) of the Hoffman reflex is associated with reduced dorsal spinal cord potassium chloride cotransporter expression and impaired spinal γ-aminobutyric acid type A receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5-hydroxytryptamine type 2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy compared with healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fiber pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

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BACKGROUND AND PURPOSEThis study was designed to clarify mechanisms responsible for the anti-allodynic effects of duloxetine in diabetes. EXPERIMENTAL APPROACHThe streptozotocin-induced diabetic rat model was used to compare the efficacy of duloxetine, 5-HT, the 5-HT2A receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)] and two antagonists (ketanserin and pruvanserin) on tactile allodynia. KEY RESULTSSystemic or intrathecal injection of duloxetine alleviated tactile allodynia in diabetic rats. The effect of systemic duloxetine was reduced by intrathecal administration of ketanserin or pruvanserin, indicating participation of spinal 5-HT2A receptors in the mechanism of action of duloxetine. In contrast to spinal delivery, systemic and local peripheral injections of ketanserin or pruvanserin alleviated tactile allodynia in diabetic rats. This effect was reversed immediately after systemic or local DOI injection. CONCLUSIONS AND IMPLICATIONSThese results support the involvement of spinal 5-HT2A receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT2A receptors depends on the level of the neuraxis at which activation takes place, with peripheral activation contributing to tactile allodynia in diabetic rats, whereas spinal activation of this receptor alleviates tactile allodynia. The development of selective peripheral 5-HT2A receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain. AbbreviationsAUC, area under the 50% PWT time curve; ECL, enhanced chemiluminescence; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride; DRG, dorsal root ganglia; i.t., intrathecal; PBS, phosphate buffered saline buffer; PWT, paw withdrawal threshold IntroductionDiabetes mellitus is an increasingly common chronic medical condition, affecting over 100 million people worldwide. Up to 60% of diabetic patients develop some form of peripheral neuropathy and around 20% will develop neuropathic pain, including spontaneous pain, paresthesia, dysethesia, hyperalgesia and allodynia (Boulton et al., 1983;Partanen et al., 1995). The current first-line treatments for painful diabetic neuropathy include anticonvulsants, tricyclic antidepressants, opioids and serotonin (5-HT) and noradrenaline reuptake inhibitors (Ziegler, 2009). Duloxetine (Cymbalta) is a 5-HT-noradrenaline reuptake inhibitor used to treat depression that also alleviates allodynia in several inflammatory and neuropathic pain models (Iyengar et al., 2004 Piesla et al., 2009;Vranken et al., 2011). Clinical studies have confirmed the efficacy of duloxetine against pain in diabetic patients (Goldstein et al., 2005;Raskin et al., 2005;Wernicke et al., 2006), and the drug has been approved by the US Food and Drug Administration for management of painful diabetic neuropathy. The sites and mechanisms of action responsible for the pain-relieving effects of duloxetine in diabetes remain unclear. Duloxetine inhibits transporters of 5-HT and n...

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