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The Journal of Neuroscience, August 13, 2003, 23(19):7262-7268

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Presynaptic Mechanism for Anti-Analgesic and Anti-Hyperalgesic Actions of -Opioid Receptors

Bihua Bie and Zhizhong Z. Pan

Departments of Symptom Research and Biochemistry and Molecular Biology, The University of Texas-MD Anderson Cancer Center, Houston, Texas 77030

Glutamate neurotransmission plays an important role in the processing of pain and in chronic opioid-induced neural and behavioral plasticity, such as opioid withdrawal and opioid dependence. -Opioid receptors also have been implicated in acute opioid modulation of pain and chronic opioid-induced plasticity, both of which are primarily mediated by µ-opioid receptors. Using whole-cell patch clamp recordings in brain slices in vitro and system analysis of pain behaviors in rats in vivo, this study investigated the functional role of glutamate synaptic transmission and-opioid receptors in two behavioral pain conditions:µ-opioid-induced analgesia (decreased pain) and µ-opioid withdrawal-induced hyperalgesia (increased pain). In the nucleus raphe magnus (NRM), a brainstem structure that controls spinal pain transmission, we found that-receptor agonists presynaptically inhibited glutamate synaptic currents in both of the two cell types that are thought to respectively inhibit or facilitate spinal pain transmission. In rats, both glutamate receptor antagonists and the agonist microinjected into the NRM attenuated µ-opioid-induced analgesia, which is most likely mediated through activation of such pain-inhibiting neurons. However, during opioid abstinence-induced withdrawal, the same doses of glutamate receptor antagonists and the agonist administered in the NRM suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal. These results demonstrate that -opioid receptors antagonize µ-receptor-induced effects in both analgesic and hyperalgesic states, and suggest inhibition of glutamate synaptic transmission as a presynaptic mechanism for the antagonism of these two µ receptor-mediated actions.

Key words: receptors; µ receptors; opioid; glutamate; analgesia; hyperalgesia; pain

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Received Feb. 21, 2003; revised May. 13, 2003; accepted May. 20, 2003.

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