Role of the spinal TrkB‐NMDA receptor link in the BDNF‐induced long‐lasting mechanical hyperalgesia in the rat: A behavioural study

Abstract

Intrathecal BDNF induces long-lasting central sensitization via a glial-likely BDNF self-regenerating mechanism, whose behavioural expression depends on downstream activation of NMDA receptors. This knowledge suggests that TrkB antagonists could represent an interesting lead for the development of novel therapeutic strategies for some chronic pain conditions.

BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis

“…Recombinant human BDNF protein (3 ng/10 μL/rat; 248-BD-025, R&D systems, Minneapolis, MN), injected intrathecally (i.t. ), was reconstituted at 25 μg/mL in 0.1 M sterile phosphate-buffered saline (PBS, pH 7.4) [27,28].…”

Pre-emptive multimodal analgesia with tramadol and ketamine–lidocaine infusion for suppression of central sensitization in a dog model of ovariohysterectomy

“… 61 In a behavioral study, chronic ketamine prevented BDNF-induced mechanical hyperalgesia in rats. 62 Likewise, systemic lidocaine at 2 mg/kg bolus significantly suppressed development of acute mechanical hyperalgesia during tonic pressure. 63 Systemic lidocaine decreased pain and morphine requirement (103.1±72.0 versus 159.0±73.3 mg) after major abdominal surgery.…”

Burst-Like Subcutaneous Electrical Stimulation Induces BDNF-Mediated, Cyclotraxin B-Sensitive Central Sensitization in Rat Spinal Cord

“…Furthermore, since the changes induced by SES in paw pressure threshold and C-reflex activity were prevented by administration of CTX-B, a drug that is unable to modify the nociceptive thresholds in normal non-sensitized mice ( Constandil et al, 2012 ), it is likely that the whole process was triggered by the release of BDNF from primary afferents due to SES. This interpretation is supported by the following observations: (i) high-frequency SES, but not low-frequency SES, of afferent sensory nerves at C-fiber intensity causes spinal release of BDNF ( Lever et al, 2001 ); (ii) intrathecal injection of BDNF produces CTX-B-sensitive enduring mechanical hyperalgesia in rats, which imitates that induced by high-frequency SES ( M’Dahoma et al, 2015 ); (iii) full-length TrkB receptors were present at somato-dendritic membranes of lamina II neurons in the rat and mouse dorsal horn ( Salio et al, 2005 ); (iv) binding of BDNF to the TrkB receptor regulates neural response and synaptic function in the dorsal horn output neurons through a variety of neuroplasticity mechanisms, including increased phosphorylation of NMDA receptor subunits NR1 ( Slack et al, 2004 ; Liu et al, 2015 ) and NR2B ( Peng et al, 2012 ; Ding et al, 2015 ; Li et al, 2017 ); (v) activation of NMDA receptors downstream to TrkB signaling is essential for behavioral expression of the mechanical hyperalgesia induced by intrathecal BDNF ( Marcos et al, 2017 ). It is then conceivable that BDNF released by C-fibers during SES application rapidly facilitates the induction of NMDA-dependent early-phase LTP in the spinal cord thereby leading to central sensitization, as reflected by the lower paw pressure threshold and the increased C-reflex activity.…”

“…In this context, inflammatory, neuropathic and other forms of chronic pain, are causally related to upregulation of a variety of pronociceptive mediators produced by neurons and glial cells in the spinal cord, i.e., glutamate ( Kawamata and Omote, 1996 ; Andó and Sperlágh, 2013 ), ATP ( Cui et al, 2014 ), cytokines ( Whitehead et al, 2010 ), neurotrophins ( Coull et al, 2005 ), which are accompanied by complex changes in dorsal horn expression of the corresponding receptors, i.e., glutamate, purinergic, cytokine, and BDNF receptors ( Latremoliere and Woolf, 2009 ). In turn, intrathecal injection of these mediators to naïve animals can induce a behavioral pain response, but only the intrathecal injection of the neurotrophin BDNF and ATP has been found to produce a significant hyperalgesic status that is maintained for several weeks ( Nakagawa et al, 2007 ; Constandil et al, 2011 ; Marcos et al, 2017 ).…”