Spinal Activation of Tropomyosin Receptor Kinase-B Recovers the Impaired Endogenous Analgesia in Neuropathic Pain Rats

Anesth Analg. 2019 Aug;129(2):578-586. doi: 10.1213/ANE.0000000000003592.


Background: Although endogenous analgesia plays an important role in controlling pain states, chronic pain patients exhibit decreased endogenous analgesia compared to healthy individuals. In rats, noxious stimulus-induced analgesia (NSIA), which is an indicator of endogenous analgesia, diminished 6 weeks after spinal nerve ligation (SNL6W). A recent study in rats with deleted noradrenergic fibers demonstrated that the noradrenergic fibers were essential to NSIA. It has also been reported that brain-derived neurotrophic factor increased spinal noradrenergic fibers. Therefore, this study examined the effect of TrkB activation, which is the receptor for brain-derived neurotrophic factor, on impaired NSIA in SNL6W rats. In addition, we also examined the effect of endogenous analgesia on acute incisional pain.

Methods: After 5 daily intraperitoneal injections of 7,8-dihydroxyflavone (7,8-DHF, TrkB agonist, 5 mg/kg), NSIA was examined by measuring the withdrawal threshold increment in the left (contralateral to nerve ligation) hindpaw at 30 minutes after capsaicin injection (250 μg) in the forepaw. K252a (TrkB antagonist, 2 μg) was administrated intrathecally for 5 days. Idazoxan (α2 adrenoceptor antagonist, 30 μg), atropine (muscarinic antagonist, 30 μg), and propranolol (nonselective β adrenoceptor antagonist, 30 μg) were administered intrathecally for 15 minutes before capsaicin injection. Microdialysis and immunohistochemistry were performed to examine the noradrenergic plasticity in the spinal dorsal horn. A hindpaw incision was performed on the left (contralateral to nerve ligation) hindpaw. Data were analyzed by 1-way analyses of variance or 2-way repeated-measures 1-way analysis of variance followed by a Student t test with Bonferroni correction.

Results: Five daily intraperitoneal injections of 7,8-DHF restored the attenuated NSIA in SNL6W rats (n = 7, P = .002; estimated treatment effect [95% CI]: 62.9 [27.0-98.7] g), with this effect blocked by 5 daily intrathecal coadministrations of K252a (n = 6, P < .001; -57.8 [-78.3 to -37.2] g). This effect was also inhibited by a single intrathecal administration of idazoxan (n = 8, P < .001; -61.6 [-92.4 to -30.9] g) and atropine (n = 8, P = .003; -52.6 [-73.3 to -31.9] g), but not by propranolol. Furthermore, 7,8-DHF increased the noradrenergic fiber in the spinal dorsal horn and the noradrenaline release in response to the capsaicin injection in the forepaw in SNL6W rats. In addition, repeated injections of 7,8-DHF prevented delayed recovery from incisional pain in SNL6W rats.

Conclusions: Spinal activation of TrkB may recover the attenuated endogenous analgesia by improving the adrenergic plasticity, thereby leading to prevention of pain prolongation after surgery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Fibers / drug effects
  • Adrenergic Fibers / enzymology
  • Analgesics / pharmacology*
  • Animals
  • Disease Models, Animal
  • Enzyme Activation
  • Flavones / pharmacology*
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / enzymology
  • Neuralgia / physiopathology
  • Neuronal Plasticity / drug effects
  • Norepinephrine / metabolism
  • Pain Threshold / drug effects*
  • Rats, Sprague-Dawley
  • Receptor, trkB / agonists*
  • Receptor, trkB / metabolism
  • Signal Transduction
  • Spinal Cord Dorsal Horn / drug effects*
  • Spinal Cord Dorsal Horn / enzymology
  • Spinal Cord Dorsal Horn / physiopathology


  • 6,7-dihydroxyflavone
  • Analgesics
  • Flavones
  • Ntrk2 protein, rat
  • Receptor, trkB
  • Norepinephrine