Newly Published
Pain Medicine  |   February 2019
α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents
Author Notes
  • From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas (M.D., S.-R.C., H.C., H.-L.P.); and the Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan, China (M.D.).
  • Submitted for publication July 8, 2018. Accepted for publication January 10, 2019.
    Submitted for publication July 8, 2018. Accepted for publication January 10, 2019.×
  • Correspondence: Address correspondence to Dr. Pan: Department of Anesthesiology and Perioperative Medicine, Unit 110, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. huilinpan@mdanderson.org. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine / Opioid
Pain Medicine   |   February 2019
α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents
Anesthesiology Newly Published on February 27, 2019. doi:10.1097/ALN.0000000000002648
Anesthesiology Newly Published on February 27, 2019. doi:10.1097/ALN.0000000000002648
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Presynaptic N-methyl-d-aspartate receptors contribute to opioid tolerance and hyperalgesia as well as neuropathic pain

  • The α2δ-1 protein subunit enhances presynaptic N-methyl-d-aspartate receptor activity

What This Article Tells Us That Is New:

  • Using mouse and rat models, it was demonstrated that α2δ-1 is essential for the increase in presynaptic N-methyl-d-aspartate receptor activity seen during chronic morphine exposure

  • Inhibiting α2δ-1 activity using gabapentin or genetically deleting the gene coding for α2δ-1 results in diminished opioid tolerance and hyperalgesia

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.