Preclinical assessment of utility of M6S for multimodal acute and chronic pain treatment in diabetic neuropathy

Previous 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. Effects 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. Acutely, 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. These 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.