BDNF but not NT-4 is required for normal flexion reflex plasticity and function

Abstract

Neurotrophins can directly modulate the function of diverse types of central nervous system synapses. Brain-derived neurotrophic factor (BDNF) might be released by nociceptors onto spinal neurons and mediate central sensitization associated with chronic pain. We have studied the role of BDNF and neurotrophin-4 (NT-4), both ligands of the trkB tyrosine kinase receptor, in synaptic transmission and reflex plasticity in the mouse spinal cord. We used an in vitro spinal cord preparation to measure monosynaptic and polysynaptic reflexes evoked by primary afferents in BDNF-and NT-4-deficient mice. In situ hybridization studies show that both these neurotrophins are synthesized by sensory neurons, and NT-4, but not BDNF, also is expressed by spinal neurons. BDNF null mutants display selective deficits in the ventral root potential (VRP) evoked by stimulating nociceptive primary afferents whereas the non-nociceptive portion of the VRP remained unaltered. In addition, activity-dependent plasticity of the VRP evoked by repetitive (1 Hz) stimulation of nociceptive primary afferents (termed windup) was substantially reduced in BDNF-deficient mice. This plasticity also was reduced in a reversible manner by the protein kinase inhibitor K252a. Although the trkB ligand NT-4 is normally present, reflex properties in NT-4 null mutant mice were normal. Pharmacological studies also indicated that spinal N-methyl-D-aspartate receptor function was unaltered in BDNF-deficient mice. Using immunocytochemistry for markers of nociceptive neurons we found no evidence that their number or connectivity was substantially altered in BDNF-deficient mice. Our data therefore are consistent with a direct role for presynaptic BDNF release from sensory neurons in the modulation of pain-related neurotransmission.B rain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are structurally related neurotrophins that act through a common tyrosine kinase trkB receptor and regulate neuronal survival and differentiation (1). In addition, it is now known that neurotrophins are powerful modulators of both peripheral and central nervous system synapses (2). Thus both basal synaptic transmission and long-term synaptic plasticity can be regulated by neurotrophins (3).In the spinal cord, a form of synaptic plasticity termed central sensitization underlies many forms of hyperalgesia, and neurotrophins play an important role in this process (4, 5). For example, the hyperalgesia and pain associated with peripheral inflammation depends on up-regulation of nerve growth factor (NGF) in inflamed tissues (6-8). NGF can directly sensitize primary afferent nociceptors expressing the trkA receptor and also indirectly increase primary afferent connectivity in the spinal cord (6, 9, 10, 11). BDNF is synthesized by trkA-positive sensory neurons, and NGF treatment dramatically increases levels of BDNF in these neurons (12). Furthermore, BDNF is anterogradely transported to the spinal terminals of nociceptive neurons where it is localized in dense core vesicles and pres...

PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

“…Noxious thermal, mechanical, and chemical (capsaicin, mustard oil) stimuli induce phosphorylation of TrkB receptors in the SDH (Pezet et al, 2002), and application of the pan-Trk inhibitor, K252a, attenuates capsaicin-induced ERK phosphorylation in the SDH (Kawasaki et al, 2004), suggesting a role of endogenous BDNF in acute pain. Indeed, the nociceptive reflex is impaired from BDNF-deficient mice (Heppenstall and Lewin, 2001;MacQueen et al, 2001). However, sequestering endogenous BDNF with a TrkB-Fc fusion protein did not affect capsaicin-induced mechanical hypersensitivity in rats (Mannion et al, 1999).…”

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

“…The effects of mature BDNF on spinal synapses is rapid and probably occurs via both pre-and post-synaptic trkB receptors and the potentiation observed is because of phosphorylation of NMDA receptor subunits Heppenstall and Lewin, 2001;Garraway et al, 2003) (Figure 2). …”

“…Nevertheless, studies using isolated spinal cords from young neurotrophin gene mutant mice have shown that the plasticity of ventral root potentials, which reflects C-fiber drive flexion reflexes, are selectively attenuated in the absence of BDNF, but not in the absence of NT-4 (Heppenstall and Lewin, 2001). A systematic examination of painrelated behaviors in BDNF heterozygote mutant mice also indicated that even reduced gene dosage of this important factor can lead to deficits in acute noxious heat sensitivity and reduced pain behaviors e.g.…”

Endogenous TrkB Ligands Suppress Functional Mechanosensory Plasticity in the Deafferented Spinal Cord

“…Unlike BDNF, NT-4 has no effect on activity-dependent synaptic plasticity or neuropathic pain (Heppenstall and Lewin, 2001;Yajima et al, 2002). To determine whether potential neuromodulatory effects of BDNF contributed to mechanosensory recovery, we gave rats bolus intrathecal injections of either IgG or TrkB-Fc (2 g of protein) on days 9 and 10 after DRI.…”