Role of the spinal TrkB-NMDA receptor link in the BDNF-induced long-lasting mechanical hyperalgesia in the rat: A behavioural study
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Date
2017
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Abstract
Background: Intrathecal/intracisternal BDNF in rodents produces longlasting
hyperalgesia/allodynia, which implies BDNF plays a role in the
establishment and maintenance of central sensitization. Both selfregeneration
of endogenous BDNF and neuroplastic modifications of
spinal NMDA receptors downstream TrkB signalling could be involved in
such enduring hyperalgesia. We investigated to what extent BDNF by
itself could participate in the generation and maintenance of mechanical
hyperalgesia using pharmacological tools.
Methods: We studied sensitivity of mechanical hyperalgesia induced by
a single intrathecal (i.t.) injection of BDNF (3 ng/10 lL i.t.) administered
at time zero, for: (1) chronic NMDA receptor inhibition with
subcutaneously implanted 7-day delivery osmotic pumps loaded with
ketamine; (2) TrkB receptor inhibition with intraperitoneal (i.p.)
cyclotraxine-B; and (3) chronic glial inhibition with repeated
propentofylline i.t. injections. Nociceptive threshold to paw pressure,
tested on days -3, 0, 3, 7, 10 and 14, was used as the index of central
sensitization. Locomotor patterns and food and water consumption were
assessed with LABORAS.
Results: Chronic ketamine prevented the mechanical hyperalgesia
induced by BDNF, without affecting locomotion and food and water
consumption. After pump depletion, a late hyperalgesic response to paw
pressure stimulation emerged, which can be lastingly antagonized by
cyclotraxine-B. Chronic propentofylline treatment irreversibly
suppressed BDNF-induced hyperalgesia.
Conclusion: Activation of NMDA receptors downstream to TrkB
signalling is essential for behavioural expression of the mechanical
hyperalgesia induced by intrathecal BDNF. However, maintenance of
the hyperalgesia depends mainly from self-regenerating glial BDNF
rather than from a NMDA receptor-dependent form of neuroplasticity.
Significance: 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.