Actions of brain‐derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat

Abstract

The aim of the current study was to investigate whether, and if so how, brain-derived neurotrophic factor (BDNF) acts to develop the spinal sensitization underlying inflammation-induced hyperalgesia. In spinal cord slice preparations from rats with inflammation induced by complete Freund's adjuvant (CFA), BDNF, but not nerve growth factor (NGF) or neurotrophin-3 (NT-3), acted presynaptically to increase the frequency of excitatory miniature EPSCs in substantia gelatinosa (SG) neurones of the CFA-treated, but not untreated rats, through activation of lidocaine (lignocaine)-sensitive, TTX-resistant Na + channels. This effect was observed in the spinal cord slices of the CFA-treated rat only 2-4 days after the CFA injection. On the other hand, the number of monosynaptic Aβ afferent inputs to the SG significantly increased 1 week after the onset of the inflammation, and this increase was significantly suppressed by treatment with anti-BDNF antiserum administered 1 day before and just after the CFA injection. In addition, the treatment with anti-BDNF antiserum significantly attenuated the CFA-induced hyperalgesia and/or allodynia. These findings, taken together, suggest that BDNF, which is considered to be released from the sensitized primary afferents, increases the excitability of SG neurones through its action on the presynaptic terminals. BDNF may thereafter induce monosynaptic Aβ afferents to the SG, thereby developing hyperalgesia and/or allodynia during inflammation.

Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of postnatal rat spinal cord

“…In keeping, pharmacological experiments have demonstrated that the plastic changes in spinal cord sensory pathways that follow inflammation, can be blocked by a trkB-IgG fusion protein sequestering BDNF . Moreover, evidence has been provided that BDNF, acting on trkB receptors, causes an increase of spontaneous glutamate release in dorsal horn lamina II, both in control animals and during inflammation (Bardoni et al, 2004;Matayoshi et al, 2005).…”

Slow modulation of synaptic transmission by brain-derived neurotrophic factor leads to the central sensitization associated with neuropathic pain

“…It has been found in the central nerve terminals of primary afferent fibers [32]; neuropathic pain-related behaviors, such as allodynia, are attenuated by blocking or sequestering BDNF [24,33]. Also, following nerve injury, the expression of BDNF and its high-affinity receptor, TrkB, are upregulated in the superficial dorsal horn [34][35][36][37][38][39].…”

“…Although it was already established that neuropathic painrelated behaviors, such as allodynia, are attenuated by blocking or sequestering BDNF [24,33], demonstrating that such manipulations prevent the development of the CCI "footprint" would be practically rather difficult. Essentially all of the works done in establishing the "footprint," which required recording and extensive data analysis from hundreds of substantia gelatinosa neurons [27], would need to be repeated after multiple in vivo intrathecal injections of BDNF blockers.…”

“…The likely role of BDNF in inducing central sensitization associated with neuropathic pain is supported by a variety of behavioral studies. For example, intrathecal BDNF is known to produce hyperalgesia [45], and neutralization of BDNF with antibodies [60], RNA antisense [33,68], or binding proteins [56,69] attenuates various types of injury-induced pain.…”

Multipotent Neurotrophin Antagonist Targets Brain-Derived Neurotrophic Factor and Nerve Growth Factor

“…Efforts to antagonize the effects of BDNF by use of anti-BDNF antiserum or a trkB-IgG construct have been successful in models of neuropathic pain and inflammatory hypersensitivity (Matayoshi et al, 2005). However, to date, no small-molecule antagonists of BDNF have been described.…”