• T Mixcoatl-Zecuatl and C G Jolivalt.
• Department of Pathology, University of California, San Diego, La Jolla, CA 92093-0612, USA.
• Br. J. Pharmacol. 2011 Sep 1; 164 (1): 159-69.

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-HT(2A) 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-HT(2A) 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-HT(2A) receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT(2A) 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-HT(2A) receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain.© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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