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

Abstract

Morphine-6-O-sulfate (M6S) is as a mixed-action mu/delta (μ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule-controlled responding to assess abuse-liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3-O-acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine-like effects. Tolerance to response rate-decreasing effects was studied in rats administered either 1.0 or 3.0 mg/kg morphine or M6S before food-reinforced operant sessions. At both unit doses, tolerance to M6S-elicited rate suppression developed more slowly than tolerance to morphine-induced reductions in response rates. To assess dependence, rats were maintained on 1.0 mg/kg morphine or 1.0 mg/kg M6S until food-reinforced response rates were stable for at least 5 days. Rats were then administered saline or increasing doses of the opioid antagonist naltrexone (NTX) (0.3, 1.0, 3.0, or 10.0 mg/kg) in order to determine antagonist-precipitated withdrawal. NTX precipitated withdrawal was similar in both morphine-maintained and M6S-maintained rats. In conclusion, the mixed μ/δ agonist activity of M6S failed to completely protect against the development of physical dependence, but delayed tolerance development to behavioral effects and resulted in decreased morphine-like subjective effects, perhaps implying a decreased abuse liability over μ agonists.

Keywords: abuse liability; delta opioid receptor (DOR); drug discrimination; mixed‐action mu/delta opioids; morphine; morphine‐6‐O‐sulfate (M6S); mu opioid receptor (MOR); physical dependence.

Figure 1

Structures of morphine hydrochloride (A), morphine‐6‐O‐sulfate (M6S; B), the 3‐O‐acetyl ester of morphine‐6‐O‐sulfate (M3A6S; C), fentanyl hydrochloride (D), and salvinorin A free base (E)

Figure 2

Failure of rats to attain criterion discriminative performance with 0.3 mg/kg M6S over approximately two months (~30 M6S and ~30 saline sessions), but rapid acquisition of 3.0 mg/kg morphine as a discriminative stimulus in these same subjects. Abscissa: percent of total responses emitted on the opioid lever. Ordinate: training sessions where saline, M6S or morphine was administered and discriminative performance was assessed

Figure 3

Left panel ‐ Discriminative stimulus effects of morphine (gray circles), fentanyl (black upward triangles), M6S (white circles), salvinorin A (black downward triangles), and M3A6S (black diamonds) in rats trained to discriminate 3.0 mg/kg morphine from saline. Abscissa: percent of total responses emitted on the morphine lever. Ordinate: dose of substitution drug in mg/kg on a logarithmic scale. “SAL” refers to saline trials, while “TD” refers to administration of the training dose of morphine. Right Panel ‐ Response rates engendered during discrimination trials by morphine and various substitution drugs. Abscissa: rate of lever pressing behavior, in responses per second. Ordinate: as described in left panel

Figure 4

Progressive tolerance to rate‐decreasing effects of daily 1.0 mg/kg (left panel) or 3.0 mg/kg (right panel) morphine (gray circles) or M6S (white circles). Abscissae: rate of lever pressing behavior, expressed as percent of saline control rates. Ordinates: Consecutive test sessions where saline was administered on sessions 1‐5, and drug was administered thereafter

Figure 5

Effects of saline or various doses of naltrexone on response rates in rats maintained on daily saline (white squares), 1.0 mg/kg morphine (gray circles) or 1.0 mg/kg M6S (white circles). Abscissa: as described in Figure 3. Ordinate: dose of naltrexone in mg/kg on a logarithmic scale. “SAL” refers to saline control trials