title: A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy.
abstract: OBJECTIVE
  This study was designed to clarify mechanisms responsible for the anti-allodynic effects of duloxetine in diabetes.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  Systemic 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
  These 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.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093-0612, USA.
authors.forename: T
authors.initials: T
authors.lastname: Mixcoatl-Zecuatl
authors.forename: C G
authors.initials: CG
authors.lastname: Jolivalt
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000068736:Duloxetine Hydrochloride; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000662:Amphetamines; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D013876:Thiophenes; D012701:Serotonin; D000068736:Duloxetine Hydrochloride; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine