Evaluation of Analgesia, Tolerance, and the Mechanism of Action of Morphine-6-O-Sulfate Across Multiple Pain Modalities in Sprague-Dawley Rats

Abstract

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.

Evaluation of morphine‐like effects of the mixed mu/delta agonist morphine‐6‐O‐sulfate in rats: Drug discrimination and physical dependence

“…First, we observed that M6S‐maintained rats (both 1.0 and 3.0 mg/kg per day) required approximately twice as many daily injections to become tolerant to rate‐decreasing effects as compared to morphine. Interestingly, these results are in close agreement with our previous in vivo studies examining tolerance to the analgesic effects of M6S and morphine . Thus, tolerance to the behavioral effects of M6S appears to develop more slowly than with morphine, both in terms of analgesic effects and in terms of schedule‐controlled responding.…”

“…Doses for M6S and M3A6S were chosen based on studies that evaluated their analgesic effects and adverse effects. Previous research in our lab and others have demonstrated that a dose above 5.6 mg/kg of M6S causes sedation and affects locomotor function in rats. Therefore, doses above 5.6 mg/kg of M6S and M3A6S were not tested in consideration of the safety of the animals.…”

“…The trend of increasing morphine‐like effects as the M6S dose is increased does suggest that M6S may elicit full morphine‐like interoceptive effects at higher doses than those presently tested. However, the fact that M6S was approximately 3‐fold more potent than morphine to elicit antinociceptive effects, but was here determined to be less potent than morphine in eliciting discriminative stimulus effects, perhaps suggests a widened therapeutic window as a function of the modification to the 6 position.…”

“…Any drug that penetrates the central nervous system will disrupt operant responding at some dose, and these disruptions are readily quantifiable as decreases in response rates when compared to control conditions. Combined with the results of previous reports knowledge gained from this study will help understand the pharmacology of mixed μ/δ opioids and foster better strategies in the design and development of novel opioids in order to engineer a safer and more effective therapeutic for chronic pain.…”

“…Thus, drug discrimination in laboratory rodents is a useful assay to determine the subjective effects of novel compounds in man. Then, the effects of chronic morphine or M6S on rates of food‐maintained operant responding were examined in order to determine the rate of tolerance development to this behavioral effect at doses in the analgesic range . Finally, after complete tolerance to rate‐decreasing effects had developed, we maintained animals on daily morphine or M6S and assessed the effects of the opioid antagonist naltrexone on response rates in order to gauge antagonist‐precipitated withdrawal as a means of determining drug dependence.…”