Chronic morphine treatment induces differential changes in presynaptic and postsynaptic NMDA receptor activity in the spinal cord

2012 ◽  
Vol 13 (4) ◽  
pp. S53
Author(s):  
H. Pan ◽  
S. Chen ◽  
Y. Zhao
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Receptor Activity ◽  
Morphine Treatment ◽  
Chronic Morphine ◽  
Chronic Morphine Treatment

scholarly journals Chronic Morphine Treatment Alters NMDA Receptor-Mediated Synaptic Transmission in the Nucleus Accumbens

1999 ◽  
Vol 19 (20) ◽  
pp. 9081-9089 ◽  
Author(s):  
Gilles Martin ◽  
Serge H. Ahmed ◽  
Thomas Blank ◽  
Joachim Spiess ◽  
George F. Koob ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Nmda Receptor ◽  
Synaptic Transmission ◽  
Morphine Treatment ◽  
Chronic Morphine ◽  
Chronic Morphine Treatment

scholarly journals α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

2019 ◽  
Vol 130 (5) ◽  
pp. 804-819 ◽  
Author(s):  
Meichun Deng ◽  
Shao-Rui Chen ◽  
Hong Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Spinal Dorsal Horn ◽  
Receptor Activity ◽  
Morphine Treatment ◽  
Chronic Morphine ◽  
Analgesic Tolerance ◽  
Spinal Dorsal ◽  
Aspartate Receptor ◽  
C Terminus ◽  
Opioid Induced Hyperalgesia

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-d-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-d-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-d-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1–bound N-methyl-d-aspartate receptors contribute to presynaptic N-methyl-d-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance. Methods Rats (5 mg/kg) and wild-type and α2δ-1–knockout mice (10 mg/kg) were treated intraperitoneally with morphine twice/day for 8 consecutive days, and nociceptive thresholds were examined. Presynaptic N-methyl-d-aspartate receptor activity was recorded in spinal cord slices. Coimmunoprecipitation was performed to examine protein–protein interactions. Results Chronic morphine treatment in rats increased α2δ-1 protein amounts in the dorsal root ganglion and spinal cord. Chronic morphine exposure also increased the physical interaction between α2δ-1 and N-methyl-d-aspartate receptors by 1.5 ± 0.3 fold (means ± SD, P = 0.009, n = 6) and the prevalence of α2δ-1–bound N-methyl-d-aspartate receptors at spinal cord synapses. Inhibiting α2δ-1 with gabapentin or genetic knockout of α2δ-1 abolished the increase in presynaptic N-methyl-d-aspartate receptor activity in the spinal dorsal horn induced by morphine treatment. Furthermore, uncoupling the α2δ-1–N-methyl-d-aspartate receptor interaction with an α2δ-1 C terminus–interfering peptide fully reversed morphine-induced tonic activation of N-methyl-d-aspartate receptors at the central terminal of primary afferents. Finally, intraperitoneal injection of gabapentin or intrathecal injection of an α2δ-1 C terminus–interfering peptide or α2δ-1 genetic knockout abolished the mechanical and thermal hyperalgesia induced by chronic morphine exposure and largely preserved morphine’s analgesic effect during 8 days of morphine treatment. Conclusions α2δ-1–Bound N-methyl-d-aspartate receptors contribute to opioid-induced hyperalgesia and tolerance by augmenting presynaptic N-methyl-d-aspartate receptor expression and activity at the spinal cord level.

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