Highlights
- •Tropomyosin receptor kinase B agonist restored impaired noradrenergic descending inhibition in spinal nerve ligation rats.
- •Tropomyosin receptor kinase B agonist did not affect spinal nerve ligation-induced hypersensitivity.
- •A decrease in GABA after painful stimulation contributes to the locus coeruleus activation.
- •Restoration of locus coeruleus responsibility may enhance the analgesic effect of pregabalin.
Abstract
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.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 7,8-dihydroxyflavone, a TrkB receptor agonist, blocks long-term spatial memory impairment caused by immobilization stress in rats.Hippocampus. 2010; 22: 399-408
- Tricyclic antidepressant amitriptyline indirectly increases the proliferation of adult dentate gyrus-derived neural precursors: An involvement of astrocytes.PLoS ONE. 2013; 8: e79371
- The role of cardiovascular activity in fibromyalgia and conditioned pain modulation.Pain. 2014; 155: 1064-1069
- Quantitative assessment of tactile allodynia in the rat paw.J Neurosci Methods. 1994; 53: 55-63
- Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction.Nat Commun. 2014; 5: 5331
- BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.Nature. 2005; 438: 1017-1021
- Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: Differential regulation of specific exons by antidepressants and corticosterone.Neuroscience. 2006; 139: 1017-1029
- TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease.J Neurochem. 2016; 136: 620-636
- Pain-induced analgesia mediated by mesolimbic reward circuits.J Neurosci. 1999; 19: 7175-7181
- Conditioned pain modulation: A predictor for development and treatment of neuropathic pain.Curr Pain Headache Rep. 2013; 17: 361
- Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery.Anesthesiology. 2007; 106 (Available at:): 557-562
- Gabapentin acts within the locus coeruleus to alleviate neuropathic pain.Anesthesiology. 2008; 109 (Available at:): 1077-1084
- Central processing of noxious somatic stimuli in patients with irritable bowel syndrome compared with healthy controls.Clin J Pain. 2010; 26: 104-109
- Repeated administration of amitriptyline in neuropathic pain: modulation of the noradrenergic descending inhibitory system.Anesth Analg. 2017; 125: 1281-1288
- Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia.Brain Res. 2016; 1634: 57-67
- Repeated administration of duloxetine suppresses neuropathic pain by accumulating effects of noradrenaline in the spinal cord.Anesth Analg. 2018; 126: 298-307
- Spinal activation of tropomyosin receptor kinase-b recovers the impaired endogenous analgesia in neuropathic pain rats.Anesth Analg. 2018 Jun 20; ([Epub ahead of print])
- An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.Pain. 1992; 50 (Available at:): 355-363
- Gabapentin loses efficacy over time after nerve injury in rats: Role of glutamate transporter-1 in the locus coeruleus.Pain. 2016; 157: 2024-2032
- Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats.Neurosci Lett. 2015; 608: 18-22
- Impaired pain-evoked analgesia after nerve injury in rats reflects altered glutamate regulation in the locus coeruleus.Anesthesiology. 2015; 123: 899-908
- Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis.J Pain. 2012; 13: 936-944
- Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression.Psychopharmacology. 2016; 233: 405-415
- Amitriptyline, but not pregabalin, reverses the attenuation of noxious stimulus-induced analgesia after nerve injury in rats.Anesth Analg. 2016; 123: 504-510
- Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: An experimental study.Pain. 2008; 139: 439-448
- Differential effect of brain-derived neurotrophic factor on high-threshold mechanosensitivity in a rat neuropathic pain model.Neurosci Lett. 2000; 278: 85-88
- The rat brain in stereotaxic coordinates.Academic Press;, Cambridge, MA:2007
- Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat.Anesthesiology. 2015; 122: 895-907
- Impaired modulation of pain in patients with postherpetic neuralgia.Pain Res Manag. 2014; 19: e19-23
- BDNF contributes to both rapid and homeostatic alterations in AMPA receptor surface expression in nucleus accumbens medium spiny neurons.Eur J Neurosci. 2014; 39: 1159-1169
- Beta-amyloid and brain-derived neurotrophic factor, BDNF, up-regulate the expression of glutamate transporter GLT-1/EAAT2 via different signaling pathways utilizing transcription factor NF-kappaB.Neurochem Int. 2003; 43: 363-370
- Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity.J Cell Mol Med. 2015; 19: 2352-2364
- Altered balance of glutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression in BDNF-deficient hippocampal neurons.J Neurosci. 2006; 26: 7189-7200
- Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms.Neuropharmacology. 2014; 81: 95-100
Takasu K, Ono H, Tanabe M: Gabapentin produces PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission in LC neurons following partial nerve injury in mice. J Neurochem 105:933–942, 2008
- Analgesic activity of certain flavone derivatives: A structure-activity study.J Ethnopharmacol. 1990; 28: 207-214
- The role of the synthetic enzyme GAD65 in the control of neuronal gamma-aminobutyric acid release.Proc Natl Acad Sci U S A. 1999; 96: 12911-12916
- Effects of chronic administration of amitriptyline, gabapentin and minocycline on spinal brain-derived neurotrophic factor expression and neuropathic pain behavior in a rat chronic constriction injury model.Reg Anesth Pain Med. 2013; 38: 124-130
- Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.Neuropsychopharmacology. 2003; 28: 53-62
- Effects of duloxetine treatment on cognitive flexibility and BDNF expression in the mPFC of adult male mice exposed to social stress during adolescence.Front Mol Neurosci. 2016; 9: 95
- Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.Curr Opinion Anaesthesiol. 2010; 23: 611-615
- 7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats.J Neurochem. 2012; 122: 800-811
Article info
Publication history
Published online: December 07, 2018
Accepted:
November 28,
2018
Received in revised form:
November 8,
2018
Received:
March 2,
2018
Footnotes
Supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Scientific and Technology of Japan (No. 26893032 and No. 16K20080 to Dr. Suto), and a research grant from Eli Lilly Japan K.K. (Hyogo, Japan)
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2018 by the American Pain Society
