Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance

Abstract

: The growth factors BDNF and GDNF are gaining more and more attention as modulators of synaptic transmission in the mature central nervous system (CNS). The two molecules undergo a regulated secretion in neurons and may be anterogradely transported to terminals where they can positively or negatively modulate fast synaptic transmission. There is today wide consensus on the role of BDNF as a pro-nociceptive modulator, as the neurotrophin has an important part in the initiation and maintenance of inflammatory, chronic, and/or neuropathic pain at peripheral and central level. At spinal level, BDNF intervenes in the regulation of chloride equilibrium potential, decreases the excitatory synaptic drive to inhibitory neurons, with complex changes in GABAergic/glycinergic synaptic transmission, and increases excitatory transmission in the superficial dorsal horn. Differently from BDNF, the role of GDNF still remains to be unraveled in full. This review resumes the current literature on the interplay between BDNF and GDNF in the regulation of nociceptive neurotransmission in the superficial dorsal horn of the spinal cord. We will first discuss the circuitries involved in such a regulation, as well as the reciprocal interactions between the two factors in nociceptive pathways. The development of small molecules specifically targeting BDNF, GDNF and/or downstream effectors is opening new perspectives for investigating these neurotrophic factors as modulations of nociceptive transmission and chronic pain. Therefore, we finally will consider the molecules of (potential) pharmacological relevance for tackling normal and pathological pain.

The cAMP Response Element- Binding Protein/Brain-Derived Neurotrophic Factor Pathway in Anterior Cingulate Cortex Regulates Neuropathic Pain and Anxiodepression Like Behaviors in Rats

“…It also alleviates anxiety and depression-like behaviors in SNI rats. Surprisingly, CREB/BDNF knockdown in the ACC significantly increases CREB and BDNF in the spinal cord, and the increased BDNF may exert its neurotrophic effects on the repair of injured peripheral nerves ( Ferrini et al, 2020 ). The intervention on the CREB/BDNF pathway in the ACC will not only relieve neuropathic pain but also alleviate the emotional dysfunction that accompanies the neuropathic pain, indicating that emotional dysfunction, induced by neuropathic pain ( Thibault et al, 2014 ), may share common pathways and that the CREB/BDNF pathway may be one of the expected targets.…”

Proteomic analyses related to inflammation and pain in children with juvenile idiopathic arthritis

“…Many proteins involved in the in ammatory process are recognized as important mediators of in ammatory pain [32], including proteins originating from neurons [33]. It has become apparent that there is an interaction between the immune and nervous system in steady state as well as under pathological circumstances.…”

2D <em>vs</em> 3D morphological analysis of dorsal root ganglia in health and painful neuropathy

“…13 Non-peptidergic nociceptors typically bind the isolectin B4 from Griffonia simplicifolia (IB4) and are immunoreactive to the LA4 antibody. 14 These neurons also express GDNF receptors RET, GFRα1, GFRα2 9,15,16 and the purinergic receptor P2X3. 17 Medium-sized DRG neurons (30-50 µm in diameter) are mainly nociceptors and give rise to fine myelinated Aδ-type primary afferent fibers displaying faster conduction velocity as compared to C fibers.…”

“… 13 Non-peptidergic nociceptors typically bind the isolectin B4 from Griffonia simplicifolia (IB4) and are immunoreactive to the LA4 antibody. 14 These neurons also express GDNF receptors RET, GFRα1, GFRα2 9 , 15 , 16 and the purinergic receptor P2X3. 17 …”