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N-methyl-D-aspartate receptors involved in morphine-induced hyperalgesia in sensitized mice
Shamseddin Ahmadi1, Hajar Golbaghi2, Ronak Azizbeigi3
1Department of Biological Science and Biotechnology, Faculty of Science, University of Kurdistan, P.O. Box 66167-15145, Sanandaj, Iran.
Abstract:
The aim of this study was to investigate role of the N-Methyl-D-Aspartate (NMDA) receptors in the decrease of morphine analgesia in mice after nociceptive sensitization. We used a hot plate test to assess effects of morphine on pain behavior in male NMRI mice. All drugs were administered through an intraperitoneal route. Sensitization schedule composed of 3-days pre-treatment of morphine (20mg/kg) followed by 5-days washout. The results showed that morphine (5, 7.5, 10 and 15mg/kg) induced a significant analgesia in normal mice. However, the analgesic effects of morphine significantly decreased at higher dose (15mg/kg) in sensitized mice. Injections of either a competitive NMDA receptor antagonist, D-AP5 (0, 0.25, 0.5 and 1mg/kg) or an NMDA receptor channel blocker (30, 60 and 120mg/kg) alone had no effect on pain behavior. However, injections of D-AP5 (1mg/kg), along with morphine over 3-days of the sensitization schedule, significantly prevented the decrease in the analgesic effect of the opioid at doses of 7.5 and 10mg/kg on the hot plate test. Similarly, injections of MgSO4 (120mg/kg), along with morphine over 3-days of the sensitization schedule, significantly prevented the decrease in analgesic effect of morphine at doses of 10 and 15mg/kg. It can be concluded that NMDA receptors are influenced by morphine during the sensitization schedule, which in turn may affect morphine analgesia after the schedule. This may further support the potential effectiveness of NMDA blockade during repeated use of morphine for control of chronic pain.
Insights
This study found that blocking N-Methyl-D-Aspartate (NMDA) receptors can prevent reduced morphine pain relief after repeated use. NMDA receptor antagonists show potential for managing chronic pain alongside morphine.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Opioid analgesia, particularly morphine, can decrease with repeated use, a phenomenon known as tolerance.
- Nociceptive sensitization is a condition that can exacerbate the decrease in morphine's effectiveness.
- N-Methyl-D-Aspartate (NMDA) receptors are implicated in various forms of plasticity and pain signaling.
Purpose of the Study:
- To investigate the role of NMDA receptors in the reduction of morphine analgesia following nociceptive sensitization.
- To determine if blocking NMDA receptors can prevent or mitigate morphine tolerance in a mouse model.
Main Methods:
- Male NMRI mice were subjected to a 3-day morphine sensitization schedule followed by a 5-day washout period.
- Pain behavior was assessed using the hot plate test after administration of varying doses of morphine.
- NMDA receptor antagonists (D-AP5) and a channel blocker (MgSO4) were administered concurrently with morphine during the sensitization phase.
Main Results:
- Morphine induced analgesia in normal mice, but its effectiveness significantly decreased in sensitized mice, especially at higher doses.
- Administration of D-AP5 (1mg/kg) or MgSO4 (120mg/kg) alongside morphine during sensitization prevented the reduction in morphine's analgesic effect in sensitized mice.
- Specific doses of NMDA receptor antagonists were effective in preserving morphine analgesia at doses of 7.5-15mg/kg.
Conclusions:
- NMDA receptors play a crucial role in the development of morphine tolerance induced by nociceptive sensitization.
- Blocking NMDA receptors during repeated morphine administration can preserve opioid analgesia.
- NMDA receptor antagonists represent a potential therapeutic strategy to enhance the efficacy of morphine for chronic pain management and prevent tolerance.