Related Experiment Video
Updated: Aug 19, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Involvement of delta 2 opioid receptors in the development of morphine dependence in mice
Y Miyamoto1, P S Portoghese, A E Takemori
1Department of Pharmacology, Medical School, University of Minnesota, Minneapolis.
Abstract:
The possible involvement of delta 2 opioid receptors in the development of morphine dependence was investigated using selective delta 2 receptor antagonists, naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII). The degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine pellet implantation. NTB administered s.c. as well as naloxone precipitated jumping and diarrhea in morphine-dependent mice. Chronic treatment with 5'-NTII (both i.c.v. and i.t. routes, 24 hr before, just before, 24 and 48 hr after morphine pellet implantation) increased the ED50 values of naloxone for jumping and diarrhea. These results suggest that both supraspinal and spinal delta 2 opioid receptors are involved in the development of physical dependence on systemically administered morphine. However, chronic treatment with NTB (s.c. route, 30 min before, 24 and 48 hr after morphine pellet implantation) failed to affect the ED50 values of naloxone for both withdrawal signs. These seemingly discrepant results suggest that continuous blockade of delta 2 opioid receptors (by a nonequilibrium and long-lasting antagonist, 5'-NTII) rather than intermittent blockade of delta 2 opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.
Insights
Selective delta 2 opioid receptor antagonists were used to investigate morphine dependence. Continuous blockade with naltrindole 5'-isothiocyanate (5'-NTII) inhibited dependence development, unlike intermittent blockade with naltriben (NTB).
Area of Science:
- Neuroscience
- Pharmacology
- Addiction Research
Background:
- Morphine dependence is a significant clinical concern.
- Opioid receptors play a crucial role in the development of physical dependence.
- Delta 2 opioid receptors are implicated in opioid-induced effects.
Purpose of the Study:
- To investigate the role of delta 2 opioid receptors in the development of morphine dependence.
- To determine if selective delta 2 opioid receptor antagonists can inhibit morphine dependence.
Main Methods:
- Morphine dependence was induced in mice via pellet implantation.
- The degree of dependence was assessed by naloxone-precipitated withdrawal signs (jumping and diarrhea).
- Selective delta 2 opioid receptor antagonists, naltriben (NTB) and naltrindole 5"-isothiocyanate (5"-NTII), were administered via various routes and schedules.
Main Results:
- Chronic administration of 5"-NTII (intracerebroventricularly and intrathecally) increased naloxone ED50 values, indicating inhibited dependence development.
- Intermittent administration of NTB (subcutaneously) did not significantly affect naloxone ED50 values.
- These findings suggest continuous blockade of delta 2 opioid receptors is crucial for inhibiting morphine dependence.
Conclusions:
- Both supraspinal and spinal delta 2 opioid receptors are involved in the development of morphine physical dependence.
- Continuous blockade of delta 2 opioid receptors, but not intermittent blockade, is effective in inhibiting the development of morphine dependence.
- The duration and nature of antagonist action (equilibrium vs. nonequilibrium) are critical factors in modulating opioid dependence.
