Is BDNF Sufficient for Information Transfer between Microglia and Dorsal Horn Neurons during the Onset of Central Sensitization?

Abstract

Peripheral nerve injury activates spinal microglia. This leads to enduring changes in the properties of dorsal horn neurons that initiate central sensitization and the onset of neuropathic pain. Although a variety of neuropeptides, cytokines, chemokines and neurotransmitters have been implicated at various points in this process, it is possible that much of the information transfer between activated microglia and neurons, at least in this context, may be explicable in terms of the actions of brain derived neurotrophic factor (BDNF). Microglial-derived BDNF mediates central sensitization in lamina I by attenuating inhibitory synaptic transmission. This involves an alteration in the chloride equilibrium potential as a result of down regulation of the potassium-chloride exporter, KCC2. In lamina II, BDNF duplicates many aspects of the effects of chronic constriction injury (CCI) of the sciatic nerve on excitatory transmission. It mediates an increase in synaptic drive to putative excitatory neurons whilst reducing that to inhibitory neurons. CCI produces a specific pattern of changes in excitatory synaptic transmission to tonic, delay, phasic, transient and irregular neurons. A very similar 'injury footprint' is seen following long-term exposure to BDNF. This review presents new information on the action of BDNF and CCI on lamina II neurons, including the similarity of their actions on the kinetics and distributions of subpopulations of miniature excitatory postsynaptic currents (mEPSC). These findings raise the possibility that BDNF functions as a final common path for a convergence of perturbations that culminate in the generation of neuropathic pain.

Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

“…The requirement for P2X4 receptors in the release of BDNF is consistent with observations that P2X4 receptor-deficient mice have impaired microglial BDNF release, possess altered BDNF signaling in the spinal cord, and they are protected from developing mechanical allodynia following peripheral nerve injury (Ulmann et al, 2008). Indeed, there is overwhelming evidence for BDNF involvement in the initiation of central sensitization associated with neuropathic pain (Biggs et al, 2010;Lever et al, 2003;Lu et al, 2007;Obata et al, 2011). However, the previous conclusions that BDNF derived from primary afferent neurons is entirely responsible for spinal nociceptive hypersensitivity has been brought into question by evidence indicating that there is a lack of primary afferent evoked BDNF release in the spinal cord after nerve injury (Lever et al, 2003), and that eliminating BDNF from primary afferents suppresses inflammatory pain but has no effect on nerve injury-induced mechanical allodynia .…”

Persistent Inflammation-induced Up-regulation of Brain-derived Neurotrophic Factor (BDNF) Promotes Synaptic Delivery of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor GluA1 Subunits in Descending Pain Modulatory Circuits

“…BDNF can up-regulate the total levels of GluA1-GluA4 and promote the trafficking of GluA1 into the synapse (26,28,31,56). In the spinal cord, BDNF released from microglia acts as a signaling link between microglia and dorsal horn neurons for neuronal hyperexcitability under neuropathic pain conditions (57,58). In the brain stem-descending pain-modulating pathway, the BDNF in the RVM is likely originated from BDNFcontaining neurons in the PAG.…”

Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

“…Concentrations of 70 -120 M GBP and 6 -60 M PGB in vitro correspond to those found in the serum of patients using these drugs (Bockbrader et al 2010;Johannessen et al 2003).…”