Primary Afferent-Derived BDNF Contributes Minimally to the Processing of Pain and Itch

Abstract

BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools. Here, we used targeted, inducible molecular approaches to characterize the expression pattern of primary afferent BDNF and the extent to which it contributes to a variety of pain and itch behaviors. Using a BDNF-LacZ reporter mouse, we found that BDNF is expressed primarily by myelinated primary afferents and has limited overlap with the major peptidergic and non-peptidergic subclasses of nociceptors and pruritoceptors. We also observed extensive neuronal, but not glial, expression in the spinal cord dorsal horn. In addition, because BDNF null mice are not viable and even Cre-mediated deletion of BDNF from sensory neurons could have developmental consequences, here we deleted BDNF selectively from sensory neurons, in the adult, using an advillin-Cre-ER line crossed to floxed BDNF mice. We found that BDNF deletion in the adult altered few itch or acute and chronic pain behaviors, beyond sexually dimorphic phenotypes in the tail immersion, histamine, and formalin tests. Based on the anatomical distribution of sensory neuron-derived BDNF and its limited contribution to pain and itch processing, we suggest that future studies of primary afferent-derived BDNF should examine behaviors evoked by activation of myelinated primary afferents.

Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain

“…Specifically, depletion of DRG macrophages prevented the upregulation of Bdnf in the DRG that occurred within 24 h of SNI. Importantly, despite reports of BDNF synthesis by microglia 45 and presumably macrophages, consistent with other findings 36,46 , our ISH analysis only detected Bdnf mRNA in sensory neurons. On the other hand, as conditional deletion of BDNF from sensory neurons has minimal to no effect on the mechanical allodynia induced by nerve injury 34,36 , to what extent the macrophage contribution to Bdnf upregulation in sensory neurons influences nociceptive processing is not clear.…”

“…As qPCR could not determine whether the increased Bdnf derived only from sensory neurons or also from surrounding non-neuronal cells, we used in situ hybridization (ISH) to examine the DRG. Figure 5d, e shows that upregulation of Bdnf mRNA is readily detected in sensory neurons one day after nerve injury (POD1), but we found no expression in surrounding nonneuronal cells, in line with our previous report 36 . Consistent with the qPCR analysis, quantification of ISH intensity in VEH-treated mice demonstrated a threefold induction of Bdnf in the ipsilateral compared with the contralateral DRG (Fig.…”

<p>Sonic Hedgehog Signaling Contributes to Chronic Post-Thoracotomy Pain via Activating BDNF/TrkB Pathway in Rats</p>

“…Although a majority of studies have indicated that increased expression of BDNF in the spinal cord induces pain hypersensitivity, [31][32][33] some studies also reported that BDNF exerted limited pronociceptive effect and even antinociceptive effect on the pain. [34][35][36] Previous studies indicated that Shh signaling activation in the cavernous and sciatic nerves up-regulated BDNF expression. 10 Liu et al found that Shh signaling activation significantly elevated BDNF expression in the spinal cord of morphine-induced hyperalgesia rats, and administration of K252, an antagonist of BDNF, attenuated the thermal allodynia induced by SAG.…”

Developing Modern Pain Therapies

“…The microglia source of BDNF has good genetic (Sorge et al, 2015), pharmacological and immunolabeling support (Ramer et al, 2007) however it remains controversial. Embryonic fate mapping experiments and in situ hybridization have suggested that BDNF is not expressed in naïve spinal microglia (Dembo et al, 2018) and sequencing evidence suggests an absence of Bdnf transcripts in spinal microglia after partial nerve injury (Denk et al, 2016), so repeating the lineage tracing experiments in the context of nerve injury will be essential for resolution. Together, microglia play an important role in increasing nociceptive sensitivity by providing pro-inflammatory factors, functioning similarly to peripheral immune cells, although their exact roles remain unclear and the pathways are not convincingly established.…”