Peripheral pain is enhanced by insulin-like growth factor 1 through a G protein–mediated stimulation of T-type calcium channels

Zhang, Yuan; Qin, Wenjuan; Qian, Zhiyuan; Liu, Xingjun; Wang, Hua; Gong, Shan Shan; Sun, Yan-Gang; Snutch, Terrance P.; Jiang, Xinghong; Tao, Jin

doi:10.1126/scisignal.2005283

Cited by 70 publications

(111 citation statements)

References 62 publications

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“…The phosphorylation sites have been identified in the intracellular domain of IGF-1R, which allow for specific binding and modulation of multiple downstream effectors [27,28]. An earlier study by Wang et al confirmed that low shear stress-induced IGF-1R phosphorylation modulates smooth muscle cell behavior and functions (proliferation and phenotype) via enhancing Akt activation [29].…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 68%

Periodic Mechanical Stress Stimulates Cav-1-Dependent IGF-1R Mitogenic Signals in Rat Chondrocytes Through ERK1/2

Tang

Jiang

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: The biological effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively over the past few years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to mechanical stimuli remain to be determined. In the current study, we analyzed the mechanisms by which periodic mechanical stress is translated into biochemical signals and verified the key role of non-integrin mechanosensors including Caveolin-1 (Cav-1), and insulin-like growth factor-1 receptor (IGF-1R) in chondrocyte proliferation. Methods: Two steps were undertaken in the experiment. In the first step, the cells were maintained under static conditions or periodic mechanical stress for 0 h and 1 h prior to Western blot analysis. In the second step, the cells were pretreated with short hairpin RNA (shRNA) targeted to Cav-1 or IGF-1R or control scrambled shRNA. Moreover, they were pretreated with their selective inhibitors methyl β-cyclodextrin (MCD) or Linsitinib (OSI-906). They were maintained under static conditions or periodic mechanical stress for 1 h prior to Western blot analysis, and for 3 days, 8 h per day, prior to direct cell counting and CCK-8 assay, respectively. Results: Periodic mechanical stress significantly induced sustained phosphorylation of Cav-1 at Tyr 14 and IGF-1R at Tyr 1135/1136 . Proliferation was inhibited by pretreatment with Cav-1 inhibitor MCD and by shRNA targeted to Cav-1 in chondrocytes in response to periodic mechanical stress. Meantime, MCD and shRNA targeted to Cav-1 also attenuated IGF-1R, and extracellular signal-regulated kinase (ERK)1/2 activation. In addition, inhibiting IGF-1R activity by Linsitinib and shRNA targeted to

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Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 68%

Periodic Mechanical Stress Stimulates Cav-1-Dependent IGF-1R Mitogenic Signals in Rat Chondrocytes Through ERK1/2

Tang

Jiang

Sun

et al. 2018

Cell Physiol Biochem

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“…Similar to GH releasing molecules such as ghrelin or GHRH [10,54], IGF-1 and its receptor IGFr1, have also been demonstrated to be involved in nociceptive processing [16,46] in adult rodents possibly by modulating neuronal excitability [74]. Interestingly, in mice overexpressing IGF-2, studies have found reduced sensory innervation of the skin, which may play a role in peripheral responsiveness [52].…”

Section: Gh Regulates Afferent Sensitization Possibly By Suppressing mentioning

confidence: 99%

“…We surprisingly did not detect any differences in the expression of the GH receptor (GHr) in the DRGs of mice inflamed at P7 (−30.6±13%) or P14 (−40.7±23.3%) compared to age-matched naïve DRGs (p>0.05). Our previous data however [24] showed a significant increase in IGFr1 at both ages, which is a known downstream mediator of GH function in other systems [57] and has also been linked to mechanical and thermal hypersensitivity after inflammation [46,74]. Therefore, to test if GH regulated the expression of IGFr1 specifically in sensory neurons, we dissociated P14 DRGs and treated individual cultures with growth hormone.…”

Section: Gh Regulates the Expression Of Igfr1 In Sensory Neuronsmentioning

confidence: 99%

“…Thus loss of GH could reduce the activation of the transcriptional repressors, subsequently permitting IGFr1 upregulation in the DRGs. IGFr1 would then have the ability to increase the responsiveness of DRG neurons to mechanical and thermal stimuli [46,74] by modulating excitability [74] or by regulating many of the transcription factors activated from IGFr1 signaling such as ELK-1, CREB, or NFAT [2,56,65; MatInspector] which can regulate the expression of various other sensory transduction receptors/channels (e.g. TRPM3, ASIC3, P2X3, TRPV1, Piezo2, etc) that are modulated during inflammation [24].…”

Section: Gh Regulates Afferent Sensitization Possibly By Suppressing mentioning

confidence: 99%

“…IGF-1 synthesis has been shown to increase after tissue injuries [16] and locally produced IGF-1 has been linked to the development of injury-induced hypersensitivity [46,74]. Moreover, IGFr1 antagonists block mechanical and thermal hyper-responsiveness during inflammation in adults [46].…”

Section: Introductionmentioning

confidence: 99%

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Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation: Erratum.

2017

PAIN

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Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRGs). However specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. GH modulates homeostasis and tissue repair after injury, but how GH effects nociception in neonates is not known. To determine if GH played a role in modulating sensory neuron function and hyper-responsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skinsaphenous nerve-dorsal root ganglion (DRG)-spinal cord preparation. Results show that inflammation of the hairy hindpaw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated via an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that following GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRGs.

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The Levels of Insulin‐Like Growth Factor in Patients with Myofascial Pain Syndrome and in Healthy Controls

Grosman‐Rimon

Vadasz

Parkinson

et al. 2020

PM&R

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Background: Insulin-like growth factor-1 (IGF-1) plays an important role in muscle maintenance and repair. The role of IGF-2 in the muscle is less clear. Objective: To compare the levels of IGF-1 and IGF-2 in participants with acute myofascial pain syndrome (MPS) versus healthy controls and to determine whether age, gender, body mass index (BMI), region of pain, and pain intensity are associated with IGF levels. Design: A case-control study design included a total of 74 participants. Setting: Hospital emergency department. Participants: Participants presenting with acute MPS (n = 43) and non-MPS controls (n = 31). Main Outcome Measures: Serum IGF-1 and IGF-2 (pg/mL) were measured in participants with MPS within 24 hours of symptom onset, and in non-MPS controls. Group and gender differences in serum IGF-1 and IGF-2 were assessed, with group and gender as factors, while controlling for age and BMI. Results: The mean IGF-1 levels were not significantly different between MPS and controls (88 554.1, confidence interval [CI],[79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97] CI,). Significant differences were also not observed in IGF-1 levels between men and women with MPS nor between men and women in the control group. Mean levels of IGF-2 were significantly lower in patients with MPS than in controls

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Peripheral pain is enhanced by insulin-like growth factor 1 through a G protein–mediated stimulation of T-type calcium channels

Cited by 70 publications

References 62 publications

Periodic Mechanical Stress Stimulates Cav-1-Dependent IGF-1R Mitogenic Signals in Rat Chondrocytes Through ERK1/2

Periodic Mechanical Stress Stimulates Cav-1-Dependent IGF-1R Mitogenic Signals in Rat Chondrocytes Through ERK1/2

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation: Erratum.

The Levels of Insulin‐Like Growth Factor in Patients with Myofascial Pain Syndrome and in Healthy Controls

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