“One coin,two aspects”: The role of IGF1R singling in chronic pain

Chronic pain is a significant public health issue and economic burden which affects a substantial portion of the global population.^1,2 Neuropathic pain and inflammatory pain are two prevalent forms of chronic pain in clinical settings, each characterized by distinct pathogenic mechanisms.^3,4 Neuropathic pain is typically precipitated by nerve injury or lesions and presents as an exaggerated pain response (including nociceptive hypersensitivity and allodynia).^5,6 Inflammatory pain results from tissue damage or inflammation, activating the immune system and sensitizing pain pathways by the release of inflammatory mediators.^7,8 The treatment of chronic pain is challenging and complex, there is an urgent and immense need to identify novel targets for maximize pain relief while minimizing side effects and risks. ⁹

IGF1R, or the insulin-like growth factor 1 receptor, is a transmembrane receptor that plays a significant role in cell growth, survival, and differentiation. IGF1R is widely expressed in tissues involved in pain modulation, including the central nervous system (CNS), peripheral nervous system (PNS), and non-neuronal tissues contributing to nociception. In CNS, IGF1R is highly expressed in laminae I-II (superficial dorsal horn), where nociceptive primary afferents synapse with secondary neurons, ¹⁰ hippocampus, ¹¹ and frontal cortex, ¹² which may contribute to pain perception and integration. Studies have demonstrated IGF1R expression in neurons, astrocytes and microglia.^13–15 In PNS, IGF1R is mainly expressed in small-diameter sensory neurons, which transmit nociceptive signals, ¹⁶ IGF1R is also expressed in Schwann cells and contributes to the development and maintenance of bone cancer pain. ¹⁷ In non- neuronal tissues, IGF1R was found to be present in synovial fibroblasts and skeletal muscle,^18,19 keratinocytes and sensory nerve endings in the skin, ²⁰ as well as gut and bladder,^21,22 which may be involved in pain perception and regulation.

IGF-1 and IGF-2 are both part of the insulin-like growth factor family, and structurally related to insulin. They are considered classical ligands of IGF1R, and have binding affinity to IGF1R 100-fold higher than insulin, their signal through IGF1R is involved in various physiological and pathological processes, including cancer, metabolism, and neurodevelopment.^23,24 As mentioned above, IGF1R has been identified as being expressed in both dorsal root ganglion (DRG) neurons and spinal neurons, playing a significant role in various pain-related conditions, distinct ligands elicit disparate mechanisms of action on IGF1R across disparate pathological stages, thereby imparting distinctive regulatory attributes to IGF1R in neuropathic and inflammatory pain. In a study of mice chronic migraine (CM) model, upregulated expression of IGF-1 in the trigeminal nucleus caudalis (TNC) region leads to enhanced phosphorylation of IGF1R on neurons, targeting and inhibiting IGF-1/IGF1R signaling pathway may offer benefits for mitigating the progression of chronic migraine. ²⁵ In mice with chronic constriction injury (CCI) of the sciatic nerve, the abnormal IGF-1/IGF1R signaling contributes to neuropathic pain by exacerbating autophagy dysfunction and neuroinflammation. ²⁶ After plantar incision, phosphorylated Akt in DRG neurons increased significantly and was suppressed by IGF1R inhibition, increased IGF-1 production can sensitize primary afferent neurons via the IGF1R/Akt pathway to facilitate pain hypersensitivity. ²⁷ Another study demonstrated that IGF-1 enhances Cav3.2 T-type channel currents through the activation of IGF1R that is coupled to a G protein-dependent PKCα pathway, thereby increasing the excitability of DRG neurons and the sensitivity to pain. ¹⁶ Spinal Cav3.2 T-type calcium channel also play a central role during the development of bone cancer pain in rats via regulation of the IGF-1/IGF1R/HIF-1α pathway. ²⁸ In addition, Schwann cell IGF1R was reported to mediate metastatic bone cancer pain in mice through the activation TRPA1 and release of reactive oxygen species. ¹⁷ Consequently, an investigation into the differential activation of the IGF1R signaling pathway and its dynamic alterations throughout the disease progression may assist in elucidating its multifaceted functions in pain.

In a recent study published in Science Translational Medicine, Jiang et al. investigates the role of Follistatin (FST) in neuropathic pain and its underlying mechanisms. They demonstrated that sensory neuron-derived FST binding to IGF1R and subsequently activates the ERK/AKT signaling pathways and enhances Nav1.7-mediated sodium channel function, leading to neuronal hyperexcitability and the development of neuropathic pain, which proposes the FST-IGF1R signaling pathway as a potential therapeutic target (Figure 1). ²⁹

Figure 1.

The pain promotion and pain resolution function of IGF1R signaling in neuropathic pain. Left: FST from large-diameter DRG neurons binds IGF1R expressed by small-diameter neurons in a paracrine manner to promote neuropathic pain in the early phase. Right: CD11c⁺ microglia in the spinal cord release IGF-1 that binds IGF1R to promote neuropathic pain relief in the recovery phase.

Follistatin (FST) is a secreted glycoprotein that was initially identified for its role in regulating follicle-stimulating hormone (FSH) secretion and its ability to antagonize members of the transforming growth factor-beta (TGF-β) superfamily, particularly activin. Beyond its reproductive functions, FST has been implicated in a wide range of biological processes, including muscle growth, inflammation, bone metabolism and neurogenesis, but whether FST contributes to chronic pain remains unclear. In a mouse neuropathic pain model of spinal nerve ligation (SNL), Jiang et al. initially examined the expression and function of FST through behavioral, quantitative polymerase chain reaction (qPCR), immunofluorescence, and electrophysiological assessments. These experiments demonstrated the crucial function of FST in DRG in the pathogenesis of neuropathic pain. Among the observed changes, the expression level of FST was found to be elevated in the mouse SNL model, with the majority of this increase occurring in type A fiber sensory neurons. The inhibition of FST expression or knockdown using Cre-dependent adeno-associated virus resulted in the attenuation of neuropathic pain and a reduction in neuronal hyperexcitability, thereby identifying a relationship between FST and neuropathic pain. Furthermore, the intrathecal administration of FST or the overexpression of FST in the mouse L4 DRG led to a notable reduction in pain domains and an increase in the expression levels of p-ERK and p-AKT in mice. This indicates that FST may contribute to the development of pain hypersensitivity by modulating the phosphorylation of ERK/AKT in the DRG.

The authors then proceeded to investigate the targets of FST action, identifying direct binding of IGF1R to FST through the use of mass spectrometry (MS), biolayer interferometry (BLI), co-immunoprecipitation (co-IP) and molecular docking analysis. Although studies have revealed the involvement of IGF1R in tissue injury or inflammation-induced pain, its role in neuropathic pain remains largely unexplored. To ascertain the involvement of DRG IGF1R in neuropathic pain, they evaluated mechanical nociceptive hypersensitivity, p-ERK and p-AKT expression levels, and alterations in DRG neuron excitability in mice. To this end, the authors intrathecally injected mice with IGF1R receptor antagonists or FST. Additionally, IGF1R receptor antagonists or FST were incubated on DRG neurons of primary cultured WT or specific knockout IGF1R mice. IGF1R receptor antagonists reduced the levels of p-ERK and p-AKT expression while alleviating the mechanical nociceptive sensitization induced by FST in mice. In a corresponding experiment, the IGF1R receptor antagonist also abrogated the FST-induced elevation in excitability of mouse primary DRG neurons. The results were consistent when IGF1R was specifically knocked down. This indicates that FST interacts directly with IGF1R to activate the ERK/AKT signaling pathway in DRG neurons, thereby inducing nociceptive hypersensitivity. As anticipated, pharmacological blockade or genetic intervention of IGF1R also resulted in the alleviation of mechanical nociception and the prolongation of the latency of the pain response in mice subjected to the SNL model.

Furthermore, molecular docking simulations demonstrated that the N-terminus of FST is the primary site for binding to IGF1R. The authors then utilized a specific designed antagonist peptide (PEP1-4) to target this binding site, and found that PEP4 effectively blocks the interaction of FST and IGF1R, significantly alleviates neuropathic pain. Additionally, they observed that the current density of Nav1.7 increased following the incubation of DRG neurons with FST. PEP4 was found to abrogate this phenomenon, yet it did not affect the IGF1-induced increase in current density. Ultimately, the authors discovered that IGF1R antagonists diminished FST-induced neuronal excitability enhancement in human DRG (hDRG) neurons, indicating a potential role and translational value of FST-IGF1R signaling in human neuropathic pain treatment. In conclusion, this work revealed a previously unidentified contribution of FST in neuropathic pain. Nevertheless, the specific mechanism of FST-IGF1R interaction and the potential of FST in human pain therapy require further validation and remain to be fully elucidated.

The studies mentioned above highlighted the facilitation role of IGF1R in different pain conditions, however, things will not always be the case. Accumulating evidence also has revealed that IGF1R signaling may contribute to the resolution of acute and chronic pain. One study demonstrated that IGF-1 was not elevated in the dorsal root ganglion (DRG) following plantar incision. However, plantar injection of IGF-1 was observed to upregulate GRK2 expression in the DRG, thereby relieving mechanical pain sensitization. ³⁰ Mice that have been treated with Streptozotocin (STZ) develop nociceptive hypersensitivity in the early stages of the experiment, which is followed by hyperalgesia and a significant reduction in systemic IGF-1 levels. ³¹ A significant alleviation of neuropathic pain was observed in diabetic subjects following an increase in circulating IGF-1. ³² The inconsistencies observed in these studies may stem from a variety of factors, such as differences in animal models, duration of observation, and the specific sites examined across the research.

In addition, in another breakthrough study published in Science, Keita Kohno et al. investigated the role of IGF-1/IGF1R signaling in peripheral nerve injury (PNI) induced neuropathic pain. The authors found that an increase in IGF-1 expression in CD11c⁺ microglia in the dorsal horn of the spinal cord after PNI has been shown to reduce neuropathic pain with pain thresholds returning to baseline levels by day 35 after PNI. ³³ At the beginning, the authors reported that after nerve injury, the number of CD11c+ microglia in the spinal dorsal horn (SDH) significantly increases, particularly after the onset of pain behavior. These CD11c+ microglia persist even after pain remission, suggesting their important role in pain recovery. Using genetically engineered mouse models, the study showed that the depletion of CD11c+ microglia prevents spontaneous recovery from pain after nerve injury. In addition, CD11c+ microglia express IGF1, and disruption of IGF-1 signaling impairs pain recovery. subsequently, genetic knockout and IGF1-neutralizing antibody were used to further confirm the function of IGF-1, deletion of the Igf1 gene in CX3CR¹⁺ cells and neutralization of IGF1 signaling prevents pain recovery, while exogenous IGF1 administration accelerates recovery. This study reveals the critical role of CD11c⁺ microglia in the remission and relapse of neuropathic pain. These cells promote pain remission through IGF-1/IGF1R signaling and maintain the pain-free state by phagocytosing myelin debris, suggesting that CD11c⁺ microglia and the IGF-1/IGF1R signaling pathway are potential therapeutic targets for neuropathic pain resolution (Figure 1). Although IGF1 has been shown to play a critical role in pain remission, the specific downstream intracellular mechanisms still remain unclear. How does IGF-1/IGF1R signaling modulate neuronal activity or inflammatory responses to alleviate pain? Further investigation into the role of the IGF-1/IGF1R signaling pathway in neurons, microglia, astrocytes, and other immune cells may help fully elucidate its pleiotropic functions.

Similar to IGF-1, IGF-2 has also been demonstrated to play an important role in pain modulation, higher IGF-2 levels are associated with increased pain severity. In a rat model of neuropathic pain induced by spared nerve injury (SNI), pulsed radiofrequency treatment significantly inhibited the development of neuropathic pain with a lasting effect through IGF-2 down-regulation and the inhibition of ERK1/2 activity primarily in microglial cells. ³⁴ Further, in a same SNI rat model, intrathecal administration of IGF-2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF-2 expression in the spinal cord. ³⁵ Although the role of IGF-2 in pain resolution is rarely reported, its expression has been demonstrated to exhibit neuroprotective effect in Huntington’s disease and Parkinson’s disease, which position IGF-2 as a promising therapeutic target to prevent or delay the progression of these disesases. ³⁶ Future researches are extensively needed to clarify IGF-2’s precise role and pathways in different pain conditions and validate its potential as therapeutic target for the treatment of pain related diseases.

So all the above studies indicate that the spatial and temporal expression patterns of IGF-1 and IGF-2 in chronic pain conditions are complex and context-dependent, involving both peripheral and central nervous system mechanisms. IGF-1 is highly expressed in pain-related regions such as the dorsal root ganglia (DRG), spinal cord, and brain (e.g. hippocampus and cortex). In the early phase of injury, IGF-1 is rapidly upregulated in peripheral tissues and sensory neurons, enhancing nociceptor excitability and contributing to pain hypersensitivity. Over time, persistent IGF-1 signaling in glial cells, including astrocytes and microglia, can promote central sensitization, thereby sustaining chronic pain. However, IGF-1 can also support pain resolution in later stages, particularly through its expression in CD11c+ microglia in the spinal cord. IGF-2, though less studied, is mainly expressed in the spinal cord and microglia, with increased expression in neuropathic pain models. Its temporal pattern suggests a role in the maintenance phase of chronic pain, and downregulation of IGF-2 has been shown to alleviate pain. While IGF-1 generally acts as a double-edged sword—both protective and pathological depending on timing and context—IGF-2 is increasingly recognized for its potential role in modulating persistent pain through central mechanisms.

One study investigated how IGF1 modulates the excitability of dorsal root ganglion (DRG) nociceptive neurons, it is interesting that acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection, chronic IGF-1 exposure (24 h) conversely reduced overall excitability while upregulating M-current density, ³⁷ the opposite effects of IGF-1 on DRG neuron may partially explain its dual role in pain modulation, increasing neuron excitability in acute phase and offering neurotrophic and neuroprotective effect in chronic phase. In diabetic mice with impaired healing due to reduced CGRP levels, engineered CGRP (eCGRP) with enhanced tissue retention restored healing by reducing inflammation and promoting tissue repair, ³⁸ so based on the pleiotropic effect of IGF-1, it may also be helpful to have engineered IGF-1 for pain resolution and wound healing in the future.

Despite significant progress in understanding the role of IGF-1/IGF1R signaling in pain regulation, critical gaps still remain, offering valuable opportunities for future research to advance this field and enhance its translational potential. First, future studies should define the spatiotemporal dynamics of IGF signaling across different pain stages (early vs. late) and anatomical regions (e.g. DRG, spinal cord, brain). Additionally, identifying molecular switches—such as ligand isoforms, receptor heterodimerization with insulin receptors, or crosstalk with pathways like mTOR or MAPK—could explain why IGF exerts pro- or anti-nociceptive effects in different scenarios. Second, while existing research mainly focuses on the DRG and spinal cord, IGF or IGF1R is also highly expressed in brain regions (e.g. hippocampus, cortex) associated with pain processing and comorbidities like depression and anxiety. Future work should explore supraspinal mechanisms, such as IGF1R modulation in the amygdala or prefrontal cortex, which may regulate affective pain dimensions. Furthermore, since chronic pain often co-occurs with cognitive deficits, IGF-1’s neuroprotective properties could be harnessed to address both conditions. Third, systemic IGF-1 administration carries risks, such as cancer progression, necessitating targeted delivery systems. Innovations could include tissue-specific agonists/antagonists (e.g. peptides or antibodies selective for nociceptive neurons or glia) and nanocarriers to enhance CNS delivery while minimizing peripheral side effects. By addressing these gaps, it’s hopeful to transform IGF-1/IGF1R from a "promising" target into a clinically actionable strategy for precision pain medicine.

Consequently, these studies collectively underscore the multifaceted roles and critical importance of IGF1R signaling in neuropathic pain, from different angles—peripheral sensitization or central pain modulation. Pain promotion and pain resolution, the seemingly opposite effects mediated by the same signaling molecule, like two aspects of a coin, albeit in different contexts. Taken together, the multifaceted functions of IGF1R signaling offer novel insights and promising avenues for pain therapy, paving the way for the development of more precise therapeutic approaches in the future.