• Jai Shankar K Yadlapalli, Navdeep Dogra, Anqi W Walbaum, Paul L Prather, Peter A Crooks, and Maxim Dobretsov.
• Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
• Life Sci. 2018 Jan 1; 192: 151-159.

AimsPrevious reports from our laboratory have established that morphine-6-O-sulfate (M6S) is a mixed μ/δ opioid receptor (OR) agonist and a potential improved alternative to morphine for treatment of chronic multimodal pain in non-diabetic rats. This study extends the antinociceptive effects of M6S and morphine in STZ-induced diabetic rats.Materials And MethodsEffects of morphine and M6S were studied across a range of pain modalities, using hot plate threshold (HPT), pinprick sensitivity threshold (PST) and paw pressure threshold (PPT) tests.Key FindingsAcutely, M6S was 3- to 5-fold more potent and 2- to 3-fold more efficacious than morphine in HPT and PST tests. No differences in analgesic drug potency/efficacy were detected in the PPT test. After 7-9days of chronic treatment, tolerance developed to the antinociceptive effects of morphine, but not to M6S, in all three pain tests. Furthermore, morphine-tolerant rats were not cross-tolerant to M6S. The selective δ-OR antagonist, naltrindole, blocked M6S-induced antinociception by 62±3% in the HPT test, 93±5% in the PST test, and 30±17% in the PPT test when examined acutely.SignificanceThese studies provide additional confirmation for the mixed μ/δ activity of M6S and demonstrate potential improved clinical utility for dual μ/δ agonists relative to morphine in treatment of diabetic neuropathy across multiple pain domains.Copyright © 2017 Elsevier Inc. All rights reserved.

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