Cingulate NMDA NR2B receptors contribute to morphine-induced analgesic tolerance

Shanelle W Ko,Jessica Quan,Min Zhuo,Long-Jun Wu,Fanny Shum

doi:10.1186/1756-6606-1-2

Abstract

Morphine is widely used to treat chronic pain, however its utility is hindered by the development of tolerance to its analgesic effects. While N-methyl-D-aspartate (NMDA) receptors are known to play roles in morphine tolerance and dependence, less is known about the roles of individual NMDA receptor subtypes. In this study, Ro 256981, an antagonist of the NMDA receptor subunit NR2B, was used to reduce the expression of analgesic tolerance to morphine. The mechanisms altered with chronic drug use share similarities with those underlying the establishment of long-tem potentiation (LTP) and behavioral memory. Since NMDA NR2B receptors in the anterior cingulate cortex (ACC) play roles in the establishment of LTP and fear memory, we explored their role in changes that occur in this region after chronic morphine. Both systemic and intra-ACC inhibition of NR2B in morphine-tolerant animals inhibited the expression of analgesic tolerance. Electrophysiological recordings revealed a significant increase in the NR2B component of NMDA receptor mediated excitatory postsynaptic currents (EPSCs), at both synaptic and extra-synaptic sites. However, there was no change in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated EPSCs. This study suggests that selective inhibition of NMDA NR2B receptors may prove useful in combating the development of analgesic tolerance to morphine and proposes a novel role for the ACC in opioid tolerance and morphine induced changes in synaptic plasticity.

Highlights

Morphine is the most widely used analgesic to treat moderate to severe pain its use is hindered by the development of physical dependence and tolerance to its analgesic effects
The effect of Ro 256981 in the anterior cingulate cortex (ACC) was abolished by one hour after microinjection (p = 0.66). These results indicate that NR2B receptors in the ACC play a role in the behavioral responses associated with opioid analgesic tolerance
We show that inhibiting NR2B receptors in the ACC can inhibit behavioral responses in tolerant animals, suggesting for the first time that this prefrontal region

Summary

Introduction

Morphine is the most widely used analgesic to treat moderate to severe pain its use is hindered by the development of physical dependence and tolerance to its analgesic effects. The utility of N-methyl-D-aspartate receptor (NMDAR) antagonists in both potentiating and prolonging the analgesic effects of morphine while attenuating analgesic tolerance and physical withdrawal symptoms has been widely reported (see [1,2,3,4,5] for review). Pharmacological manipulation of NMDA receptor activity may pose a useful strategy for increasing the efficacy of morphine as a treatment for chronic pain in the future. NMDARs are composed of NR1, NR2 (A, B, C, and D) and NR3 (A and B) subunits in the central nervous system. It is known that the NR2A and NR2B subunits predominate (page number not for citation purposes)

Methods

Results

Discussion

Conclusion