Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. A lack of understanding of its aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect and possible mechanism of action of a serotonin reuptake inhibitor, fluoxetine, in streptozotocin-induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia, compared with control mice. Fluoxetine (10 and 20, but not 5 mg/kg, i.p.) injected into diabetic mice produced an antinociceptive effect in both the tail-immersion and hot-plate assays. The percentage maximum possible effect (% MPE) produced by fluoxetine (20 mg/kg, i.p.) was significantly lower in diabetic mice than in control mice. The antinociceptive effect of fluoxetine (20 mg/kg) in diabetic mice was dose-dependently potentiated by pindolol (5 and 10 mg/kg, i.p., a selective 5-HT1A/1B receptor antagonist), attenuated by ritanserin (1 and 2 mg/kg, i.p., a selective 5-HT2A/2C receptor antagonist) and remained unaffected by ondansetron (1 and 2 mg/ kg, i.p., a selective 5-HT3 receptor antagonist) in both test systems. These results suggest that fluoxetine-induced antinociception primarily involves serotonin pathway modulation through 5-HT1 and 5-HT2 receptors, but not through 5-HT3 receptors, in the chronic pain associated with streptozotocin-induced diabetic neuropathy. Further, the potentiation of the antinociceptive effect of fluoxetine by pindolol indicates the usefulness of a combination of an antidepressant and a 5-HT1A/1B receptor antagonist in the treatment of diabetic neuropathic pain in humans. (C) 2004 Elsevier B.V. All rights reserved.