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Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

C G Jolivalt, Y Jiang, J D Freshwater, G D Bartoszyk, N A Calcutt
Diabetologia 2006, 49 (11): 2775-85
16924480

AIMS/HYPOTHESIS: We investigated spinal and peripheral kappa opioid systems in diabetic rats.

MATERIALS AND METHODS: Dynorphin A, N-methyl-D-aspartate (NMDA) and kappa opioid receptor (KOR) were measured in spinal cord, dorsal root ganglia, peripheral nerves and foot skin of control and streptozotocin-induced diabetic rats by immunoassay and Western blotting. Behavioural assessments of paw tactile sensitivity and formalin-evoked hyperalgesia were performed in normal and diabetic rats before and after treatment with asimadoline.

RESULTS: Dynorphin A protein levels were significantly increased in peripheral nerves and footpad skin of diabetic rats. Dynorphin A exhibits both anti- and pro-nociceptive properties depending on activation of either KOR or NMDA receptors. Spinal protein levels of these receptors were not changed by diabetes, while KOR levels in the sciatic and peroneal nerves were significantly increased. Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats. Both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats were acutely ameliorated by asimadoline. To confirm that the effect of asimadoline was related to its property as KOR agonist, diabetic rats were pretreated with the selective KOR antagonist nor-binaltorphimine. Intraplantar nor-binaltorphimine abolished the ability of asimadoline to alleviate tactile allodynia in diabetic rats. Systemic and intrathecal nor-binaltorphimine partially inhibited the effect of asimadoline against formalin-evoked hyperalgesia in diabetic rats.

CONCLUSIONS/INTERPRETATION: Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy.

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