Chronic pain represents a pervasive global health challenge, causing significant disability and socioeconomic burdens ^[1][2][1,2]. With over 30% of the world’s population grappling with chronic pain, it has emerged as a formidable public health concern, posing substantial challenges for both researchers and clinicians ^[3][4][3,4]. Compounding the issue is the inadequacy of existing drug treatments, which often fall short in terms of efficacy and tolerability, leaving more than half of patients with chronic pain without sufficient relief ^[5][6][7][8][5,6,7,8]. Groundbreaking research in neuroscience has led the World Health Organization to recognize chronic pain as a disease characterized by intricate functional and structural changes in the brain, neuroinflammation, and increased sensitivity of the central nervous system (CNS) to nociceptive input—central sensitization (CS) ^{[9][10][11][12][13]}[9,10,11,12,13]. In essence, chronic pain not only represents prolonged acute pain but also involves maladaptive neuroplastic changes and sensitization of the nociceptive pathways in the nervous system, extending beyond a simple pain–damage association [14].

In recent years, intensive research has focused on understanding the biochemical and molecular alterations contributing to chronic pain. One promising avenue of exploration centers around the brain-derived neurotrophic factor (BDNF) gene, which influences circulating levels of BDNF, and has been implicated in initiating and/or perpetuating neuronal hyperexcitability, maladaptive neuroplasticity, and disinhibition at different levels of nociceptive pathways [15]. BDNF assumes a central role in promoting brain homeostasis and neuronal survival, and also serves as a critical regulator of synaptic plasticity [16]. Despite its crucial role in maintaining normal physiological functions, a less positive perspective emerges concerning chronic pain, where mounting evidence suggests a pro-nociceptive role for BDNF ^[17][18][17,18]. Consequently, BDNF is increasingly acknowledged as a pivotal perpetuating factor in chronic pain.

2. The Physiological Role of BDNF

Since its discovery, BDNF has garnered extensive attention as one of the most extensively studied neurotrophins, owing to its multipotent impacts on various physiological and pathological functions within the nervous system. Recognized for its robust protective actions promoting brain homeostasis, neuronal survival, synaptogenesis, plasticity, and cognitive function ^{[16][19][20][21]}[16,19,20,21], BDNF exhibits activity throughout all stages of development and aging ^[22][23][22,23]. BDNF plays a crucial role in initiating compensatory processes that facilitate recovery and/or alleviate chronic adverse effects caused by injury or disease in the nervous system [19]. Like other neurotrophins, BDNF is initially synthesized as a pre-pro-protein. The pre-protein undergoes rapid cleavage to form pro-BDNF, which then assembles in homodimers ^[24][26]. The pro-BDNF can be subsequently cleaved by extracellular proteases at synapses and converted to mature BDNF ^[25][27]. BDNF exerts its biological functions via two distinct classes of receptors: the high-affinity tropomyosin receptor kinase B (TrkB) and the low-affinity p75 neurotrophin receptor (p75NTR). Pro-BDNF exhibits a preference for binding to p75NTR, while mature BDNF preferentially binds the TrkB receptor. In general, binding to TrkB receptors allows BDNF to modulate and promote neuronal survival, neuroprotection, and long-term potentiation (LTP)—a form of long-term synaptic plasticity in nociceptive pathways ^[26][28]. Conversely, binding to p75NTR receptors may regulate neuronal apoptosis, axonal process pruning, and long-term depression (LTD) ^[27][28][29,30]. The contrasting effects of BDNF/TrkB and BDNF/p75NTR signaling form a delicate “yin-yang” system that finely manipulates neuroplasticity and neuronal excitability ^[29][31]. The functionality of the central nervous system (CNS) is intricately tied to available BDNF expression. Predominantly synthesized and expressed in various neuronal cells of the brain, such as sensory neurons and motor neurons ^[30][31][32][33,34,35], BDNF is also produced, to a lesser extent, in non-neuronal cells such as glial cells and immune cells ^[33][34][36,37]. Available BDNF was found in different regions of the brain, including the neocortex, pyriform cortex, amygdala, hippocampus, claustrum, thalamus, striatum, hypothalamus, and brainstem ^[30][35][33,38]. In addition, circulating BDNF derives from both peripheral and cerebral sources ^[36][37][38][39,40,41]. 

3. The Role of BDNF in Patients with Chronic Pain

3.1. The Role of BDNF in Central Sensitization

Chronic pain is known to be associated with CS, a process by which the nociceptive signals of neurons at every level of nociceptive pathways are gradually enhanced ^[39][53]. CS is responsible for both hyperalgesia and allodynia. At the cellular level, CS occurs in part as a result of enhanced and more efficient synaptic communication between neurons, which primarily involves the reshaping of neuronal circuits, neuronal hyperexcitability, and a reduction in synaptic inhibition ^[40][41][54,55]. Given its essential role throughout the nervous system, BDNF has been implicated in the induction and maintenance of the CS. For example, the activation of BDNF/TrkB signaling has been linked to increased pain signaling mechanisms ^[42][57]. BDNF, upon release from the dorsal root ganglia, engages with TrkB receptors located on primary afferent nerve endings and post-synaptic tracts in the spinal cord. This interaction serves to amplify and potentiate ascending sensory signals, contributing to the perpetuation of CS. As expected, pain signaling mechanisms can be reversed through intrathecal administration of TrkB inhibitors, which attenuates nociceptive response ^[43][44][58,59]. It is crucial to recognize that CS involves an activity-dependent increase in the excitability of dorsal horn neurons ^[40][54], and BDNF contributes to this process by promoting a gradual increase in neuronal excitability and synaptic plasticity in the spinal dorsal horn ^[45][46][47][60,61,62].  Persistent CS has been described as a maladaptive neuroplasticity process in chronic pain ^[48][49][65,66]. BDNF can regulate synaptic plasticity in an activity-dependent manner, contributing to LTP ^[50][51][67,68]. LTP involves neuronal adaptation at the presynaptic (e.g., increased ability to produce neurotransmitters) and postsynaptic (e.g., increased ability to bind neurotransmitters to receptors) levels, resulting in enhanced synaptic efficiency and, consequently, an increase in the excitability of neuronal pathways ^[52][53][54][69,70,71]. The synapses are a critical link in inter-neuronal connections, and an increase in their number can facilitate the transmission of nociceptive signals between neurons, potentially contributing to CS ^[55][72]. However, BDNF knockout specimens exhibited a decrease in preganglionic synaptic innervation density to sympathetic neurons, suggesting that BDNF has the ability to increase synaptic density [22]. Finally, dysfunction in the descending inhibitory nociceptive modulation pathways emerges as a crucial contributor to CS. Recent studies have unveiled reduced intracortical inhibition in different pain populations compared to healthy subjects, with this reduction being associated with more severe pain symptoms ^{[56][57][58][59]}[77,78,79,80]. Disinhibition of GABAergic and glycinergic synaptic transmission in nociceptive circuitry is crucial to the generation of chronic pain. Centrally, BDNF can weaken GABAergic inhibitory synapses by reducing the expression of potassium-chloride cotransporter 2 (KCC2), thus suppressing the intrinsic inhibitory circuits ^[46][60][61][61,81,82]. 

3.2. Neuroinflammation Drives Chronic Pain via Glial-Derived BDNF and CS

While acute inflammation is responsible for triggering acute pain sensations, neuroinflammation is supposed to play an important role in the chronification and persistence of pain ^[62][63][84,85]. This neuroinflammation is initiated by the activity-dependent release of glial activators, including neurotransmitters, chemokines, and proteases. This release stems from the central terminals of primary afferent neurons or is prompted by the disruption of the blood–brain barrier. Neuroinflammation is characterized by the activation of glial cells such as microglia and astrocytes, the infiltration of immune cells, vasculature changes, and an increased release of inflammatory and glial mediators like cytokines, chemokines, and BDNF ^[64][86]. These glial mediators can significantly regulate both excitatory and inhibitory synaptic transmission, thereby contributing to CS and enhanced chronic pain states. In the spinal cord and brain, glial cells also produce nerve growth factors and neurotrophins, such as BDNF and basic fibroblast growth factor (bFGF), which can affect neuronal function and may contribute to neurotoxicity in several brain pathologies [19]. In fact, the expression of neurotrophins is often upregulated in chronic inflammatory diseases due to their involvement in energy homeostasis ^[65][88]. For example, microglial activation following peripheral nerve injury upregulates purinergic receptors, especially P2 × 4R, leading to p38-MAPK phosphorylation and subsequent BDNF release ^[66][89]. This microglial-derived BDNF has been implicated in facilitating neuropathic pain and morphine hyperalgesia ^[67][68][90,91].  A key player in inflammatory activation is the nuclear factor-kappa B (NF-κB), a transcription factor that triggers the expression of pro- and anti-apoptotic genes ^[69][99]. Remarkably, the binding of BDNF to the TrkB receptor serves as a trigger for the induction of the NF-κB expression. Furthermore, chronic inflammatory pain has been reported to induce an upregulation of TrkB mRNA and protein expression in the dorsal horn ^[70][100]. An additional layer of complexity arises from a p75NTR-mediated effect on NF-κB expression, as evidence suggests that peripheral inflammation induces an upregulation of pro-BDNF and p75NTR in the spinal cord ^[71][72][101,102]. With the activation of p75NTR, pro-BDNF can activate several downstream signaling pathways, including extracellular signal-regulated kinase (ERK)1 and ERK2, NF-κB, and c-Jun N-terminal kinase (JNK) pathways, further promoting the neuroinflammatory state ^[73][74][75][103,104,105]. These signaling pathways can trigger a series of changes, including neuronal hyperexcitability, LTP, maladaptive neuroplasticity, and an imbalance in excitatory/inhibitory neurotransmission—all of which are intricately involved in the process of CS (Figure 1). This cycle persists as long as the stressor exists, potentially evolving into a serious chronic pain state. Hence, neuroinflammation may drive chronic pain via CS, which can be induced and maintained by cytokines, chemokines, BDNF, and other glia-produced mediators.