Background Morphine-6-O-sulfate (M6S) is a mixed μ-/δ-opioid receptor (OR) agonist and potential alternative to morphine for treatment of chronic multimodal pain. Method To provide more support for this hypothesis, the antinociceptive effects of M6S and morphine were compared in tests that access a range of pain modalities, including hot plate threshold (HPT), pinprick sensitivity threshold (PST) and paw pressure threshold (PPT) tests. Results Acutely, M6S was 2 – 3-fold more potent than morphine in HPT and PST tests, Specifically, derived from best-fit analysis of dose-response relationships morphine / M6S ED50 ratios (lower, upper 95%CI) were 2.8 (2.0, 5.8) in HPT and 2.2 (2.1, 2.4) in PST tests. No differences in analgesic drug potencies were detected in the PPT test (morphine / M6S ED50 ratio 1.2 (95%CI: 0.8, 1.4). After 7–9 days of chronic treatment, tolerance developed to the antinociceptive effects of morphine, but not to M6S, in all three pain tests. Morphine-tolerant rats were not cross-tolerant to M6S. The antinociceptive effects of M6S were not sensitive to κ-OR antagonists. However, the δ-OR antagonist, naltrindole, blocked M6S-induced antinociception by 55 ± 4% (95%CI: 39, 75) in the HPT test, 94 ± 4% (95%CI: 84,105) in the PST test, and 5 ± 17% (95%CI: −47, 59) or 51 ± 14% (95%CI:14, 84; 6 rats per each group) in the PPT test when examined acutely or after 7 days of chronic treatment, respectively. Conclusions Activity via δ-ORs thus appears to be an important determinant of M6S action. M6S also exhibited favorable antinociceptive and tolerance profiles compared to morphine in three different antinociceptive assays, indicating that M6S may serve as a useful alternative for rotation in morphine-tolerant subjects.

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Existing literature concerning the effect of experimentally-induced diabetes on pain thresholds in rodent models remains controversial. In this work, we describe a phenotypical switch from streptozotocin-induced pinprick hypoalgesia to hyperalgesia observed in the same laboratory, in the same strain of rats, obtained from the same vendor, and measured by the same technique carried out by the investigators. This switch was observed around January 2015, at the time when there was a change in the diet of rats at the Radley North Carolina Charles River facility. These data support the contention that diet may significantly modify disease progression, including progression of signs of diabetic neuropathy.