Pain Medicine  |   November 2016
AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain
Author Notes
  • From the Department of Anesthesiology (C.S., D.H.), Institute of Pain Medicine (D.H.), The Third Xiangya Hospital, Central South University, Changsha, China; Departments of Anesthesiology, Perioperative Care and Pain Medicine (H.Y.L., R.Y., D.X., M.L., M.N., A.S., E.R.-P., J.W.) and Neuroscience and Physiology (J.W.), New York University School of Medicine, New York, New York; and New York University (N.P.), New York, New York.
  • Submitted for publication September 22, 2015. Accepted for publication August 8, 2016.
    Submitted for publication September 22, 2015. Accepted for publication August 8, 2016.×
  • Address correspondence to Dr. Wang: Departments of Anesthesiology, Perioperative Care and Pain Medicine and Neuroscience and Physiology, New York University School of Medicine, Alexandria Life Science Building, 450 East 29th Street, Room 823, New York, New York 10016. Jing.wang2@nyumc.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 / Basic Science / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   November 2016
AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain
Anesthesiology 11 2016, Vol.125, 1030-1043. doi:10.1097/ALN.0000000000001336
Anesthesiology 11 2016, Vol.125, 1030-1043. doi:10.1097/ALN.0000000000001336
Abstract

Background: AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive.

Methods: The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. The authors measured the effect of AMPAkines on sensory and depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. The authors asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain’s reward and pain circuitry, can be a target for AMPAkine analgesia.

Results: Systemic administration of CX546 (n = 13), compared with control (n = 13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05 ± 1.30 g [mean ± SEM] vs. 0.62 ± 0.13 g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0 ± 15.5 vs. 156.7 ± 18.5 s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81 ± 1.91 vs. 0.50 ± 0.03 g; control, n = 6; CX546, n = 8) and persistent postoperative pain (spared nerve injury) models (50% withdrawal threshold of 3.85 ± 1.23 vs. 0.45 ± 0.00 g; control, n = 7; CX546, n = 11). Blocking AMPA receptors in the NAc with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione inhibited these pain-relieving effects (50% withdrawal threshold of 7.18 ± 1.52 vs. 1.59 ± 0.66 g; n = 8 for PI groups; 10.70 ± 3.45 vs. 1.39 ± 0.88 g; n = 4 for spared nerve injury groups).

Conclusions: AMPAkines relieve postoperative pain by acting through AMPA receptors in the NAc.