BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs

Abstract

Brain-derived neurotrophic factor (BDNF) is up-regulated and released in the dorsal horn following peripheral inflammation and has therefore been implicated in spinal mechanisms of sensitization. Despite these observations, the mechanisms associated with such a role for BDNF are not yet fully determined. Here, we investigate the effect of BDNF on dorsal root-evoked synaptic transmission in lamina II neurons. In a transverse spinal cord slice preparation from neonatal rats (P1-15), the whole cell patch-clamp technique was used to record from these neurons. Brief application of BDNF (50-200 ng/mL) facilitated the evoked synaptic currents; they remained enhanced even after BDNF was washed out. A significant minority of cells was minimally affected by BDNF and consistent with this, not all neurons in lamina II were immunoreactive for the tyrosine kinase (trk) B receptor. No facilitation was elicited when N-methyl-d-aspartate (NMDA) receptors were blocked with D-APV, when the postsynaptic NMDA receptors were selectively blocked with intracellular MK-801, or when postsynaptic neurons were loaded with BAPTA. Additionally, inhibiting phospholipase C (PLC) or protein kinase C (PKC) prior to BDNF application completely blocked facilitation. However, once synaptic current underwent BDNF-induced facilitation, the PKC inhibitors failed to reverse the effect, suggesting that PKC is needed for initiation, but not maintenance of BDNF-induced facilitation. These results demonstrate that BDNF functions at the spinal level to enhance synaptic efficacy in an NMDA receptor-dependent manner and requires the action of the PLC/PKC pathway. This action of BDNF may contribute to central sensitization and exaggerated pain states.

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

“…We went on to use the noncompetitive NMDAR blocker (ϩ)-5-methyl-10,11-dihydro-5 H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801) in our recording pipette solution to test this hypothesis. We and others (Arvanov et al, 2000;Garraway et al, 2003) have found that intracellular dialysis with MK-801 (1 mM) blocks postsynaptic NMDA-induced (but not CNQX-sensitive) currents in opiate-naive cells. Intracellular MK-801 does not occlude the ability of bath-applied APV to eliminate the increased frequencies of mEPSCs recorded in lamina I cells from opiate-tolerant rats, however (Fig.…”

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). …”

Neurotrophin-3 Suppresses Thermal Hyperalgesia Associated with Neuropathic Pain and Attenuates Transient Receptor Potential Vanilloid Receptor-1 Expression in Adult Sensory Neurons

“…Finally, because the NT-3 was delivered intrathecally, one cannot exclude a potential effect of NT-3 on central sensitization events that impact on the development of thermal hyperalgesia (for review, see Melzack et al, 2001;Romanelli and Esposito, 2004). Although not the focus of this study, our previous work has shown that this form of NT-3 delivery mitigates the level of BDNF expressed by primary sensory afferents and linked to central sensitization events (Groth and Aanonsen, 2002;Garraway et al, 2003;Lever et al, 2003). The degree to which other molecules or cell types involved in this process are similarly influenced remains to be elucidated.…”