dynorphins and Diabetic-Neuropathies

We investigated spinal and peripheral kappa opioid systems in diabetic rats.. 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.. 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.. Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy.

Topics: Acetamides; Analgesics; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dynorphins; Female; Immunohistochemistry; Pain Threshold; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reference Values; Streptozocin

We evaluated the antinociceptive effect of Gosha-jinki-gan, a Kampo medicine including processed Aconiti tuber, and its mechanism in streptozotocin-induced diabetic mice. Gosha-jinki-gan (0.1-1.0 g/kg, p.o.) showed a more potent antinociceptive effect in diabetic mice than in non-diabetic mice. The antinociceptive effect of Gosha-jinki-gan (0.3 g/kg, p.o.) in diabetic mice was inhibited by administration of either anti-dynorphin antiserum (5 microg, i.t.) or nor-binaltorphimine (10 mg/kg, s.c.), a kappa-opioid antagonist. The antinociceptive activity of Gosha-jinki-gan (0.3, 1.0 g/kg, p.o.) was decreased by excluding processed Aconiti tuber. Furthermore, the antinociceptive effect of processed Aconiti tuber (0.03, 0.1 g/kg, p.o.) was also shown to be enhanced in diabetic mice. These results suggest that the increased antinociceptive effect of Gosha-jinki-gan in diabetic mice is partly derived from the action of processed Aconiti tuber and that it is based on stimulation of spinal kappa-opioid receptors via dynorphin release. Gosha-jinki-gan was considered useful for treating painful diabetic neuropathy.

Topics: Analgesics; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drugs, Chinese Herbal; Dynorphins; Immune Sera; Male; Mice; Pain Measurement; Time Factors

Intravenous infusion of lidocaine has a pain-relieving effect in patients with painful diabetic neuropathy. We measured plasma beta-endorphin (beta-EP), dynorphin immunoreactivity (DYN), and met-enkephalin (MET) before and after lidocaine infusion in 8 patients with painful diabetic neuropathy and in 10 controls. The pretreatment level of beta-EP and DYN was identical in the two groups. After lidocaine, beta-EP increased in diabetic patients from 3.4 to 5.5 pmol/L (median) (p less than 0.02) and in controls from 3.4 to 5.0 pmol/L (p less than 0.02). The concentration of DYN was stable, and MET was undetectable before and after lidocaine. Lidocaine reduced symptoms and pain score in diabetic patients was uncorrelated with the changes in beta-EP. Intravenous lidocaine increased plasma beta-EP and diminished complaints in patients with painful diabetic neuropathy.

Topics: Adult; beta-Endorphin; Diabetic Neuropathies; Dynorphins; Endorphins; Female; Humans; Lidocaine; Male; Middle Aged; Pain; Radioimmunoassay