In the early 1950's, NGF was discovered by Rita Levi-Montalcini in a tumor tissue [1]. The discovery of NGF was considered a landmark achievement in neurobiology. Since then, the diverse roles of NGF were determined in multiple era including the pain field. NGF belongs to a large family of proteins that include, in mammals, neurotrophin-3, neurotrophin-4/5 and brain-derived neurotrophic factor [2]. NGF is important for the survival, growth and differentiation of sympathetic and sensory afferent neurons during development and in the modulation of nociception in adulthood [1]. It is expressed in neuronal and non-neuronal tissues. In more detail, it is widely expressed in the central nervous cells, peripheral Schwann cells, glands, endothelial cells, immune cells and skeletal muscles [3]. Notably, there is shift in the role of NGF from neuronal growth to the regulation of the sensitivity of the peripheral nervous system to noxious stimuli [4]. NGF has two receptors including the high affinity receptor, tropomyosin receptor kinase A (TrkA) and the low affinity receptor p75 neurotrophin receptor (p75NTR) [5]. Through its interaction with the high-affinity receptor TrkA, NGF suppresses the synthesis of p75. This neurotrophic protein is produced as pro-NGF that has more affinity to p75NTR compared to NGF that binds with higher affinity to TrkA [5]. TrkA receptor is highly expressed in dorsal root ganglion (DRG) neurons during embryogenesis and its role declines post-natally [6]. Accordingly, NGF is a major contributor to pain signaling and transmission [2,7]. In this regard, it was found that rats develop hyperalgesia when degradation of NGF is blocked by matrix metalloproteinases-2 inhibitor through a peripheral mechanism [8]. The role of NGF in neuronal development and the perception of localized tissue pain has been highlighted in multiple studies [2]. Also, investigators found that increased NGF levels are linked to inflammation, persistent pain, injuries, and discomfort [7]. To add, multiple studies showed that NGF is a marker for the peptidergic nociceptors that express TrkA compared to non-peptidergic nociceptors that express glial cell line-derived neurotrophic factor [9]. Furthermore, several lines of evidences implicated the role of NGF in different types of pain such as inflammatory, neuropathic, cancer, orofacial, musculoskeletal, and low back pain (LBP) [10–13]. In fact, earlier reports pointed to the critical role of NGF-mediated signaling in the initiation and maintenance of chronic pain [2]. Thus, this review is written to shed light on the role of NGF and its signaling in different types of pain.

NGF plays a key role in nociception through several mechanisms including the release of inflammatory mediators, increase in the activity and availability of many nociceptive ion channels and receptors [14]. The binding of NGF to TrkA increases the availability of nociceptive receptors such as transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), N-methyl-D-aspartic acid, and P2X purinoceptor 3 as well as nociceptive transmitters such as substance P and calcitonin gene-related peptide (CGRP) [15,16]. Thus, NGF plays a crucial role in peripheral and central sensitization. It sensitizes nociceptors directly in the short term and/or changes gene expression in the long term [2]. Earlier reports showed that NGF binds to TrkA receptor and participates in the initiation and maintenance of nociception through several intracellular signaling pathways, including mitogen-activated protein kinases (MAPKs)/extracellular signal-regulated kinases and phosphoinositide-3-kinase(PI3K) [14]. Furthermore, NGF increases the release of serotonin, histamine, prostaglandin E2, and NGF itself, that collectively binds to their receptors on the peripheral terminals of nociceptors [17]. Also, it sets off a cascade of events that cause nociceptive pain. Furthermore, TrkA binds NGF which is then retrogradely delivered to the cell bodies of neurons. Within these cell bodies, it regulates the expression of TRPV1, bradykinin receptors, voltage-gated sodium channels, acid sensing ion channel 2/3, and other receptors [18]. The nociceptive receptors on the surface of these cells that are involved in nociception trigger peripheral sensitization and increase pain perception [19]. Meanwhile, central sensitization is produced by changes in gene expression induced by NGF-TrkA signaling [2]. In conclusion, NGF plays a key role in pain perception by regulating the expression of genes related to pain, controlling the activity of key channels/receptors in pain and increasing the pro-inflammatory mediators (Fig. 1).

Elevated levels of NGF have been associated with various pain states making it a target for pain management [3,5]. Accumulating pieces of evidence have shown that the available drugs (i.e., opiates and non-steroidal anti-inflammatory drugs [NSAIDs]) that are used for the treatment of chronic pain leads to long-term side effects such as cardiac, gastrointestinal, or renal adverse effects, suggesting the need to look for other alternatives [5,16]. Antibodies or neutralizing medicines that target NGF signaling and its ability to modulate pain in the long term, have been studied in animal models. Under the request to license the subcutaneous injection of 2.5 mg tanezumab, the Food and Drug Administration (FDA) approved its use on March 2, 2020 [79,80]. NGF inhibitors are safer and more cost-effective than joint replacement surgery, the conventional alternative treatment for knee and hip OA [79,80]. Multiple approaches were established for targeting NGF to relive pain such as preventing NGF binding, activation or inhibiting of TrkA binding/signaling and sequestration of free NGF [2,5]. NGF inhibitors were used as analgesics in chronic pain conditions such as chronic LBP and OA with better outcomes compared to NSAIDs [13]. Also worth mentioning is the importance of pointing to the different signaling of NGF in the acute and chronic phases of pain. For example, it was revealed that there is an increase in p75NTR-mRNA level in the chronic phase of the experimental model of autoimmune encephalomyelitis leading to an elevation in the p75NTR to TrkA at the chronic phase of this model [81]. Also, the expression of NGF protein increased slightly during the acute phase whereas the expression of TrkA in the brains of mice was stable during this phase [81]. Additionally, several reports showed that NGF drives local neuronal sprouting and increases the excitability of the nervous system (promotes sensitization of neurons) which is a key process in many conditions of chronic pain [2]. These findings indicate the importance of tailoring drugs that are used in the acute phase differently than the ones used for the chronic phase. Hirose et al. [12] discussed the development of analgesics targeting NGF/TrkA signaling, noting that this approach can be effective for treating intractable pain without the adverse effects that are commonly associated with traditional analgesic drugs. Also, several phase 2/3 studies have been done that target NGF and TrkA inhibitors. Furthermore, humanized anti-NGF mAbs (i.e., tanezumab, fulranumab, and fasinumab) were used in phase III trials in OA [82]. Additionally, the use of anti-NGF antibodies in patients suffering from knee OA improved stiffness, physical function, and patient global assessment [68]. Chang et al. [2] reported the effectiveness of NGF inhibitors for neuropathic and other types of pain, such as cancer and visceral pain. Peach et al. [49] found that the co-receptor for NGF is responsible for the transfer of signals to TrkA receptors, and that neuropilin 1 antagonism in nociceptors is a new approach for NGF-mediated pain. Also, another study demonstrated that development of abnormal somatosensory behavior was prevented by anti-NGF, suggesting its beneficial effect in the treatment for central pain [83]. Another important aspect in designing valuable drugs is to understand the dual roles of NGF as a pro-inflammatory and anti-inflammatory mediator which is dependent on the type and expression of NGF receptors, cellular context, and the stage of the inflammatory process. Understating these roles is crucial to tailor the inhibition of NGF in the right place and to avoid inhibiting NGF when it has an anti-inflammatory effect. Providing more detail, El-Hashim et al. [84] pointed to the role of NGF (when administered by inhalation or intracerebroventricularly) in cough and airway obstruction in guinea pigs by increasing the phosphorylation of TrkA receptors in the bronchi. On the other hand, it was shown that the expression of anti-inflammatory mediators such as IL-10 can be induced by NGF [85].

Despite the promising analgesic efficacy of anti-NGF mAbs, their development has been complicated by safety concerns, particularly regarding their long-term use. These concerns include the possibility of aggravating peripheral neuropathies and joint issues. Also, the use of anti-NGF mAbs (mainly tanezumab) in the treatment of OA was correlated with some side effects in clinical trials such as rapidly progressive OA of the knee and hip joints [13] or neurological effects [86]. Also, Bernard [87] used NGF vaccine in a mouse model of OA (destabilization of the medial meniscus) and reported the effectiveness of this vaccine in pain reduction.

Although the evidence of the efficacy for NGF inhibitors in knee OA is robust, the incidence of adverse effects increases with higher doses, longer exposure, and concomitant use of NSAIDs. In patients with musculoskeletal pain, according to Katz et al. [46], the intravenous administration of 200 μg/kg tanezumab plus an oral placebo twice a day showed analgesic effects with some adverse effects. Lane and Corr [40] discussed the efficacy of NGF inhibitors in reducing musculoskeletal pain and reported some adverse effects associated with the use of these inhibitors, such as accelerated arthropathy. Thus, the FDA halted all anti-NGF trials due to reports of rare cases of rapidly progressive joint degeneration that necessitated joint replacement, especially in those co-treated with NSAIDs [38].

As discussed in this review, the use of anti-NGF therapy showed promising effects in alleviating different types of pain. At the same time, there are adverse effects for using this therapy. More research is needed to find out routes for applying anti-NGF directly to the site of pain and to decrease its systemic side effects. Nanoparticles can be useful in this regard. To add, combinational therapy using anti-NGF therapy with other drugs can be good area for future research. Also, there is a need to explore the efficacy of anti-NGF therapy in the long term. Additionally, it would be very beneficial if scientists could design and tailor personalized NGF therapies based on the proteomics, genetic, and metabolomics analysis of patients. Finally, more research is needed to elucidate the differential mechanisms of NGF in acute and chronic pain in order to tailor drugs specifically for each case.