Tropomyosin Receptor Kinase B Receptor Activation in the Locus Coeruleus Restores Impairment of Endogenous Analgesia at a Late Stage Following Nerve Injury in Rats

J Pain. 2019 May;20(5):600-609. doi: 10.1016/j.jpain.2018.11.008. Epub 2018 Dec 8.


A rat model of neuropathic pain at 6 weeks after spinal nerve ligation (SNL6w) exhibits both mechanical hypersensitivity and impaired noxious stimuli-induced analgesia (NSIA). Repeated treatment with antidepressants can produce antihypersensitivity and restore NSIA. To examine the involvement of a brain-derived neurotrophic factor-mediated mechanism, a tropomyosin receptor kinase B (TrkB) agonist, 7,8-dihydroxyflavone (DHF), was administered to SNL6w rats (5 mg/kg/d for 5 days). Mechanical hypersensitivity was evaluated using the von Frey filament test and paw pressure test. NSIA was examined by measuring the change in the hind paw withdrawal threshold 30 minutes after painful stimulation induced by capsaicin injection into the fore paw. Changes in the concentrations of glutamate and GABA in the locus coeruleus area were measured by in vivo microdialysis. DHF treatment did not affect mechanical hypersensitivity, although it restored NSIA by reducing GABA release in response to the fore paw capsaicin injection. DHF treatment did not alter the baseline concentration of glutamate or GABA. These findings suggest that DHF treatment restored the stimuli-response activity of the locus coeruleus without affecting the tonic activity of the locus coeruleus. The brain-derived neurotrophic factor-TkB signaling is also involved in the NSIA-restoring effect of amitriptyline. PERSPECTIVE: This article demonstrates that repeated treatment with TrkB agonist, DHF, restored endogenous analgesia. Repeated amitriptyline treatment showed similar effect via TrkB-mediated mechanisms, and the effect may be independent from the effect of antihypersensitivity. This effect of TrkB activation is promising for patients with chronic pain with impaired descending inhibition.

Keywords: 7,8-Dihydroxyflavone; GABA; endogenous analgesia; locus coeruleus; spinal nerve ligation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Disease Models, Animal
  • Flavones / pharmacology*
  • Glutamic Acid / metabolism
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Locus Coeruleus / drug effects*
  • Locus Coeruleus / metabolism
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Pregabalin / pharmacology
  • Random Allocation
  • Rats, Sprague-Dawley
  • Receptor, trkB / agonists*
  • Receptor, trkB / metabolism
  • Spinal Nerves / injuries*
  • gamma-Aminobutyric Acid / metabolism


  • 6,7-dihydroxyflavone
  • Analgesics
  • Flavones
  • Glutamic Acid
  • Pregabalin
  • gamma-Aminobutyric Acid
  • Receptor, trkB