Skip to main content
Download PDF

Musical therapy attenuates neuroma pain by modifying leptin expression

BMC Complementary Medicine and Therapies volume 22, Article number: 316 (2022) Cite this article

Abstract

Background

Accumulating evidence reveals that music therapy appears to help patients with pain. However, there is a limited understanding of the underlying mechanisms. Several studies indicate that leptin level has a crucial relationship with acute and chronic pain. Herein, we evaluated the effects of music stimulation and the potential roles of adipokines (leptin) in pain behaviors.

Methods

We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. Adult male Sprague–Dawley rats were randomly assigned to one of the three groups (n = 6):group 1 (GC), TNT with white noise; group 2(GM), TNT with music; and group 3(GH), TNT. White noise and music stimulation was given once a day following surgery until the end of the study (42nd day). Pain behavioral tests were carried out before surgery and on the 3rd, 10th, 14th, 21st, 28th, 35th, and 42nd days after surgery. At the end of the observation period, we analyzed the histological samples of blood, spinal cord, and prefrontal cortex to investigate the role of leptin in pain behaviors modulated by white noise and sound stimulation.

Result

Music therapy might improve the pain of TNT rats. Music stimulation ameliorated paw withdrawal thermal latency (PWTL) from the 3rd day after the surgery while the mechanical pain was improved 21 days after the operation.Music stimulation also increased leptin expression in the spinal cord, prefrontal cortex.White noise had no obvious effect.

Conclusion

Music therapy might improve the pain of TNT rats. Besides, music stimulation ameliorated TNT-induced pain behaviors and affected leptin expression.

Peer Review reports

Introduction

A rise in limb amputations has been attributed to an increase in the incidence of trauma, peripheral vascular/nerve disorder, and limb malignancies. Amputation is a strategy applied to save a life in emergencies. Nonetheless, intractable postamputation pain (PAP) is challenging in clinical practice [1, 2]. Many studies suggest that the level of leptin is linked to both acute and chronic pain [3,4,5,6]. In the past two decades, music therapy has been widely used in clinical treatment, particularly for individuals suffering from depression, anxiety, and other mental illnesses [7, 8]. Although music therapy is not extensively utilized in patients with pain, studies reveal that music therapy has a positive effect on different types of pain [9, 10]. By releasing various bioactive molecules known as adipokines, such as leptin and adiponectin, adipose tissue acts as a vital endocrine organ [11]. Leptin is a 16 kDa hormone primarily produced by fat cells and secreted into the bloodstream; it was identified by positional cloning of the ob gene, a gene responsible for the development of obesity in ob/ob mice [12]. In recent years, leptin has been largely studied and characterized. Leptin is mostly known for proinflammatory activities [13]. Nevertheless, whether leptin causes pain or relieves pain remains controversial. This study aims to investigate the effects of different music on neuroma pain in rats and potential underlying mechanisms mediated by adipokines (leptin).

Materials and methods

Experimental animals

Adult male Sprague–Dawley rats (200–250 g) were procured from the Shanghai Laboratory Animal Center at the Chinese Academy of Science. Rats were initially housed in cages within the number upper limit and had free access to food and water. The cages were 47.5 cm in length, 35.0 cm in width, and 22.0 cm in height. Rats were maintained on a 12/12 h light/dark cycle (lights on 7:30 AM–7:30 PM). Animals were placed in individual cages after surgery. This study was carried out in compliance with the ARRIVE guidelines. All experimental protocols were approved by the Animal Care and Use Committee of Shanghai Sixth People’s Hospital affiliated with Shanghai Jiao Tong University (ethics certificate number:20160226) and performed as per the National Institutes of Health guidelines for the Care and Use of Laboratory Animals.

We established animal models as follows.The animal model of tibial neuroma transposition (TNT) was adopted as described by Dorsi et al [14]. Rats were deeply anesthetized using sodium pentobarbital via intraperitoneal injection (50 mg/kg). The tibial nerve of the rat was dissociated from the proximal 8 mm of the heel bifurcate to the distal 1 mm of the foot bifurcate, then ligated at the proximity of the plantar bifurcation with a 6–0 silk suture. Through a subcutaneous tunnel, the transected nerve terminal was gently pulled to a part 2 cm superior to the lateral malleolus and fixed beneath the skin 8-10 mm superior to the lateral malleolus. In the sham-operated rats, only the tibial nerve was dissociated and kept intact. A small piece of connective tissue was ligated and passed through the subcutaneous tunnel as per the method described above.

Experiment 1: To evaluate the effect of sound stimulation on neuroma pain, rats were randomly assigned to one of the three groups (n = 6): Group 1 (GC), TNT with white noise; group 2(GM), TNT with music; and group 3(GH),TNT. The evulation of the neuroma pain described by Dorsi et al. was used with minor modifications [14]. Briefly, the trial comprised 10 repetitive applications of a von Frey filament (15 g for 1–2 s) to the neuroma position at intervals of 1 to 2 min. White noise and music stimulation were administered once a day after surgery until the end of the study (42nd day). Pain behavioral tests were carried out before surgery and on the 3rd, 10th, 14th, 21st, 28th, 35th, and 42nd days after surgery. The rats of GH were placed in the room for the same duration, yet without any sound stimuli.

Experiment 2: To investigate the role of leptin in pain behaviors modulated by white noise and sound stimulation.

The rats were sacrificed after the behavior test on the 42nd day,the end of the observation period.We analyzed the histological samples of blood, spinal cord, and prefrontal cortex. Leptin levels in plasma were assayed using Rat Leptin ELISA kit (Crystal Chem Inc., Chicago, IL, USA) following the manufacturer’s protocols.The concentration of leptin in the spinal cord and prefrontal cortex was measured by Western blotting.

Music stimuli

The acoustic stimuli towards the subjects of the different groups were conducted in a soundproofed room with the ambient sound pressure of 40 dB SPL. The animals were unrestrained in a cage 60 cm below the loudspeaker for the acoustic stimuli. The GM group TNT rats were exposed to a piece of traditional Chinese music “LiangZhu” played by the Erhu with the intensity between 50 dB SPL and 55 dB SPL monitored by a ¼-inch microphone linked to a sound level meter (Microphone: 2520, SLM: 824, Larson Davis, Depew, NY, USA). The GC was exposed to the white noise with the intensity of 52 dB SPL. The animals of these two groups were exposed for 30 min per day and the total duration of the acoustic exposure was 42 days. The rats of GH were placed in the room for the same duration, yet without any sound stimuli.

Evaluation of pain behaviors

  1. 1.

    Von Frey's up-down method. The behavioral tests were performed in a quiet and appropriate room by an experienced observer blinded to the different treatments. The rats were allowed to adjust to the testing environment for 20 min before testing. The evaluation of the neuroma pain approach described by Dorsi et al [14] was used with minor modifications. The trial comprised 10 repetitive applications of a von Frey filament (15 g for 1–2 s) to the neuroma position at intervals of 1 to 2 min. The paw withdrawal threshold was measured using the von Frey up-down method described by Chaplan et al [15]. The test began with a middle filament in the series (2.0 g). An ascending series of von Frey filaments of logarithmically incremental force (0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, and 15.0 g; Stoelting) were applied to the lateral plantar surface of the hind paw. A positive response was a rapid withdrawal and/or licking of the paw immediately after stimulus application. Whenever a positive or negative response occurred, the testing proceeded for five more stimuli after the first change in response, and the pattern of responses was converted to a 50% paw withdrawal threshold (50% PWT) as described by Sun et al. [6].

  2. 2.

    Paw withdrawal thermal latency (PWTL). According to the Hargreaves method, the rats were placed in plexiglass chambers, and a radiant beam of light was applied to the hind paw through a glass floor [16]. Paw withdrawal latencies were recorded in duplicate per paw. A third measurement would be taken if the second latency recorded was not within 64 s of the first. The values of the two closest latencies were averaged to establish the overall latency to withdrawal.

Histology analysis

Rats were deeply anesthetized using an intraperitoneal injection of 100 mg/kg sodium pentobarbital and blood was collected by cardiac puncture. Subsequently, the spinal cord and prefrontal cortex of all rats were harvested and immediately stored at -80℃, to be processed for use in real-time quantitative PCR or Western blotting. The same was done with blood samples.

  1. 1.

    Enzyme-linked immunosorbent assay. After the pain behavior test, blood was collected 42 days after the operation. The plasma was separated by centrifugation at 5000 g for 5 min and the supernatants were obtained for subsequent protein analysis. Rat Leptin ELISA kit (Crystal Chem Inc., Chicago, IL, USA) was used to analyze the leptin levels in plasma.

  2. 2.

    Western blotting. In tissue protein extraction buffer (Thermo Fisher), the obtained spinal cord or prefrontal cortex was homogenized with a protease inhibitor cocktail (Roche). The BCA Protein Assay Kit was used to establish the protein concentrations of samples. Thereafter, the proteins were separated using the SDS-PAGE, then transferred to PVDF membranes (Merck Millipore). The membranes were cut prior to hybridisation with antibodies by the location of the target protein according to the pre staining results.After blocking with 5% bovine serum albumin at room temperature for 1 h, the membranes were incubated overnight at 4℃ with the following primary antibodies: anti-leptin(1:1000, rabbit polyclonal IgG; Invitrogen) and anti-β actin (1:1000, mouse monoclonal IgG; Santa Cruz). Afterward, the membranes were incubated with HRP-conjugated secondary antibodies (1:5000; HuaAn Biotechnology) at room temperature for 1 h. The membranes were rinsed using Tris-buffered saline and 0.1% Tween 20 between the above steps. Eventually, blots were detected via enhanced chemiluminescence substrate solution (ThermoFisher). In the chemiluminescent instrument darkroom, the blotting membranes were exposed to the X-ray Film,then printed out, scanned (Imacon 949) and quantified using the ImageJ software (version 2.0.0, National Institutes of Health, Rockville, MA, USA).

Statistical analysis

All datas were expressed as means ± SEM.Statistical analyses were performed using statistical packages (GraphPad Prism 5, GraphPad, San Diego, CA). The Student’s t-test was used to compare the difference between two groups, whereas a two-way ANOVA test was used to compare the difference among three groups. A P value of less than 0.05 (P < 0.05) was considered statistically significant.

Results

Music stimulation ameliorates TNT-induced pain behaviors

All rats assigned to different groups exhibited similar baselines of pain behaviors before surgery (Fig. 1A, B; P > 0.05). After the operation, All the TNT rats developed increased responsiveness to mechanical and thermal stimuli at the neuroma area compared to the baselines on the 3rd day after the operation (P < 0.01). After receiving music stimuli three days after the surgery, PWLT of GM group TNT rats significantly increased compared to that in the other two groups (F = 43.24, P < 0.01). The effect lasted to the 42nd day. But the significant difference of mechanical pain presented from the 21st day (GC and GH vs GM:8.12 ± 8.23 and 7.70 ± 0.22 vs 12.42 ± 0.26,P < 0.01) to the 42nd day(GC and GH vs GM:8.08 ± 1.10 and 8.10 ± 0.25 vs 12.42 ± 0.27,P < 0.01). There was no statistical difference among the three groups of 50% PWT until the 21st day (GC and GH vs GM:4.04 ± 0.33 and 4.04 ± 0.33 vs 6.77 ± 0.39,P < 0.01). The effect also lasted to the 42nd day. At the end of the experiment, we noted that music stimuli ameliorated PWLT from the 3rd day and the mechanical pain improved 21 days after the operation in GM group rats. Both effects lasted until the 42nd day (Fig. 1A, B). At the same time, white noise demonstrated no remarkable effect.

More leptin expression was associated with improved pain behaviors in the music stimulation groups

On the 42nd day after the behavior test, leptin expression in peripheral blood among the three groups were significantly different (Fig. 2, F = 21.25,P < 0.01). Leptin expression in plasma in the GM group was significantly higher than that in the other two groups (Fig. 2,GC and GH vs GM:320.60 ± 72.69 and 164.70 ± 64.40 vs 672.10 ± 256.90,*,#P < 0.01). Meanwhile, leptin expression in the the prefrontal cortex increased in GM, and reduced in GH. This was confirmed by the findings of Western blot. Significant differences were observed among GM, GC, and GH (Fig. 3A,B,C&D,*P < 0.01), however, no significant difference was found between GC and GH (P > 0.05). Besides, we found no significant difference in leptin expression among the three groups in the spinal cord.

Fig. 1
figure 1

A Effects of music stimulation on paw withdrawal latency to thermal heat induced by TNT surgery. No significant difference was observed between the three groups at baseline (P > 0.05). TNT surgery reduced the response time of paw withdrawal latency to thermal heat on the neuroma site at all test time points after surgery in GC and GH. A slight change was noted in GM. (*P < 0.05). GM compared with GC and GH, All rats assigned to different groups  6 for each group. B. Effects of music stimulation on behavioral pain induced by TNT surgery. TNT surgery decreased the 50% paw withdrawal threshold in response to mechanical stimuli to the hind paw plantar after surgery, no significant difference was noted among the three groups during the first 14 days after the operation (P > 0.05). Music stimulation reversed it from 21st day to the 42.nd day (*P < 0.05)

Full size image
Fig. 2
figure 2

Leptin level in plasma after 42 days in each group. GM concentration was significantly higher than that of the other two groups. A significant difference in the Leptin level was evident between GM and GH, GM and GC (*,#P < 0.01)

Full size image
Fig. 3
figure 3

Effects of music stimulation on expression of leptin receptor in the spinal cord and prefrontal cortex on 42.nd day. A and B Western blotting showing a significantly upregulated expression of leptin in the GM group in the prefrontal cortex. No significant difference was noted in the spinal cord. C and D Westen blot of the leptin in spinal cord and cortex of TNT rats. The membranes were cut prior to hybridisation with antibodies.We confirmed that music stimulation influences the leptin changes. In conclusion, no significant difference was noted in leptin expression among the three groups in the spinal cord (Fig. 3A P > 0.05). The difference between GM and the other two groups was statistically significant in prefrontal cortex (Fig. 3B*P < 0.01)

Full size image

Discussion

The most representative type of chronic pain is neuropathic pain. It causes long-term spontaneous pain and produces various accompanying emotional disorders (including anxiety, depression, etc.) and cognitive impairment. In our experiment, we found music therapy relieves neuroma pain. White noise had no significant effect. Over the last 4 decades, research on the effects of music on the brain has remarkably advanced [17]. For instance, Wiśniewska discovered that music therapy can relax old horses and relieve pain caused by degeneration [10]. Despite numerous clinical reports on the benefits of music in pain management under different conditions more than 10 years ago [9, 18, 19], the underlying neuronal mechanisms remain unknown. Music therapy is globally used in clinical treatment, specifically in patients with depression, anxiety, and other psychological disorders. It influences the sympathetic and parasympathetic systems by the heart rate. Besides, it is responsible for the emotional excitability of the body [20, 21]. Notably, we demonstrated smooth music can increase pain threshold and leptin expression in TNT mice. The crucial aspect of music is based on sound vibration, i.e., due to its deep penetration into the brain and body, it positively or negatively affects the mood and emotions at both the behavioral and neuronal levels [22]. In recent years, the impact of leptin on pain has been a hot topic of research. Lim et al. reported that leptin related nociceptive behavior was due to its promotion of nerve injury, thereby indicating a cellular relationship between the spinal effect and the cellular mechanism mediated by NMDA receptor of neuropathic pain [23, 24]. Many studies, though mostly in vitro, confirmed leptin’s “bad reputation”. However, some studies pointed out that leptin has a positive effect on cartilage repair and pain relief. Fu R et al. reported that leptin advanced cell proliferation and chondrocyte genetic expression in a dose-dependent manner [25]. Li et al. found that lack of leptin receptor gene may cause loss of bone mass in the vertebra [26]. This may be related to pain caused by osteoarthritis and intervertebral disc degeneration. Leptin is primarily secreted by adipose tissue. Under normal circumstances, adipose tissue rarely produces extra leptin; however, it raises in some pathological states such as inflammation [27]. Paiva ES et al. found that patients with fibromyalgia and overweight /obesity had lower leptin levels, compared with the controls [28]. Some researches suggested leptin plays a significant role in the regulation of energy balance, neuroendocrine system, immune function,which is achieved by affecting the central nervous system and peripheral tissues [29, 30]. Leptin receptors are highly expressed in areas including hypothalamic cortex, hippocampus and amygdala [31, 32]. In some brain studies, leptin plays an antidepressant role in stress models, which may be related to its function of regulating dopaminergic neurotransmission [33, 34]. The experiments of peripheral and intrahippocampal injection proved that leptin has direct antidepressant properties [35, 36]. In the researches of neurological diseases such as Parkinson's disease, Alzheimer's disease and multiple sclerosis, it is found that leptin shows neuroprotective properties [37,38,39]. Some studies showed this neuroprotective effects in Parkinson's disease have been determined through in vivo and in vitro studies [37, 40].

In our study, leptin expression increased in the prefrontal cortex, and blood in the GM group rats. Among the three groups, we found no difference in leptin expression at the medulla spinalis. We selected the prefrontal cortex (PFC) as the target for studying leptin concentration. The findings displayed a positive expression in GM compared to that of the other two groups. The prefrontal cortex is crucial in pain processing, which is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray, thalamus, amygdala, and basal nuclei. It changes during acute and chronic pain [41]. Music regulates pain responses in different parts of the CNS. In addition to animal research, this field is of significance in clinical research. When listening to pleasurable music, Dobek found increased activity in brain regions i.e., parts of descending pain modulatory system [42]. Additional studies indicate that PFC changes can be reversed after a successful pain control [43, 44].

Neuropathic pain and its complications induce extreme pain in patients and severely influence the quality of life. Music intervention is a type of non-drug therapy with a long history. It is clinically utilized as an auxiliary therapy for postoperative recovery and relieving postoperative pain. Researchers believe that this may influence the sympathetic and parasympathetic nervous systems via sound vibration [20, 45, 46]. In addition,mental disorder can influence the experience of pain, impacting its perception, affective response and the interpretation of physical symptoms.Liu et al. suggested that pain and depression tend to occur simultaneously and share some common neural circuits and neurotransmitters [47]. Angioli R et al. demonstrated that anxiety state is highly related to pain perception, music therapy can relieve anxiety so as to reduce pain [48]. All in all, pain is not an emotionally pure experience, but always accompanied by emotional suffering and depression. We consider that music therapy may prevent stress depression in rats with nerve injury, and stimulate the brain tissue to secrete leptin, which played a neuroprotective role, so as to reduce their pain sensitivity,which would be our follow-up experiments.

Conclusion

In contrast with behavioral pain outcomes, our findings suggest that the higher the leptin level in tissues, including peripheral blood and cerebral cortex, the higher the mechanical and thermal pain thresholds.

According to the findings obtained in the neuroma pain model, we conclude that graceful music influence leptin concentration both in the peripheral and central nervous systems. Our work revealed that soothing music can improve neuroma pain in TNT rats via the leptin pathway. Moreover, we provide a mechanism that may yield beneficial effects of music on pain conditions. Adipokines are potential targets for the treatment of neuropathic pain, this should be confirmed by additional research.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

References

  1. Ephraim PL, Wegener ST, MacKenzie EJ, Dillingham TR, Pezzin LE. Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Arch Phys Med Rehabil. 2005;86(10):1910–9.

    Article  PubMed  Google Scholar 

  2. Chapman Richard, Vierck Charles J. Postamputation pain epidemiology, mechanisms, and treatment. J Pain Res. 2013;6:121–36.

    Google Scholar 

  3. Tian Y, Wang S, Ma Y, Lim G, Kim H, Mao J. Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain. Pain. 2011;152(6):1263–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Segar AH, Fairbank JCT, Urban J. Leptin, and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain-an in vitro study in a bovine model. Eur Spine J. 2019;28(2):214–23.

    Article  PubMed  Google Scholar 

  5. Kinfe TM, Buchfelder M, Chaudhry SR, et al. Leptin and associated mediators of immunometabolic signaling: Novel molecular outcome measures for neurostimulation to treat chronic pain. Int J Mol Sci. 2019;20(19):4737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sun L, Lv Y, Tian J, et al. Regular swimming exercise attenuated neuroma pain in rats: involvement of leptin and adiponectin. J Pain. 2019;20(9):1112–24.

    Article  CAS  PubMed  Google Scholar 

  7. Dileo C. Effects of music and music therapy on medical patients: a meta-analysis of the research and implications for the future. J Soc Integr Oncol. 2006;4(2):67–70.

    Article  PubMed  Google Scholar 

  8. Risch M, Scherg H, Verres R. Music therapy for chronic headaches evaluation of music therapeutic groups for patients suffering from chronic headaches. Schmerz. 2001;15(2):116–25.

    Article  CAS  PubMed  Google Scholar 

  9. Cepeda MS, Carr DB, Lau J, Alvarez H. Music for pain relief. Cochrane Database Syst Rev. 2006;19(2):CD004843.

    Google Scholar 

  10. Wiśniewska M, Janczarek I, Wilk I, Wnuk-Pawlak E. Use of music therapy in aiding the relaxation of geriatric horses. J Equine Vet Sci. 2019;78:89–93.

    Article  PubMed  Google Scholar 

  11. Smitka K, Maresova D. Adipose tissue as an endocrine organ: An update on the pro-inflammatory and anti-inflammatory microenvironment. Prague Med Rep. 2015;116:87–111.

    Article  PubMed  Google Scholar 

  12. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32.

    Article  CAS  PubMed  Google Scholar 

  13. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dorsi MJ, Chen L, Murinson BB, Pogatzki-Zahn EM, Meyer RA, Belzberg AJ. The tibial neuroma transposition (TNT) model of neuroma pain and hyperalgesia. Pain. 2008;134(3):320–34.

    Article  PubMed  Google Scholar 

  15. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63.

    Article  CAS  PubMed  Google Scholar 

  16. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77–88.

    Article  CAS  PubMed  Google Scholar 

  17. Craig JD. The effects of musical training and cerebral asymmetries on the perception of an auditory illusion. Cortex. 1979;15(4):671–7.

    Article  CAS  PubMed  Google Scholar 

  18. Dileo C. Effects of music and music therapy on medical patients: a meta-analysis of the research and implications for the future. J Soc Integr Oncol. 2006;4(2):67–70.

    Article  PubMed  Google Scholar 

  19. Risch M, Scherg H, Verres R. Music therapy for chronic headaches Evaluation of music therapeutic groups for patients suffering from chronic headaches. Schmerz. 2001;15(2):116–25 (German).

    Article  CAS  PubMed  Google Scholar 

  20. Acharya UR., Joseph KP, Kannathal N, Min LC, Suri JS. Heart rate variability. Advances in cardiac signal processing. Springer, Berlin, Heidelberg. 2007. p. 121–65.

  21. Von Borell E, Langbein J, Després G, et al. Heart rate variability as a measure of autonomic regulation of cardiac activity for assessing stress and welfare in farm animals—a review. Physiol Behav. 2007;92(3):293–316.

    Article  Google Scholar 

  22. Mitterschiffthaler MT, Fu CH, Dalton JA, Andrew CM, Williams SC. A functional MRI study of happy and sad affective states induced by classical music. Hum Brain Mapp. 2007;28(11):1150–62.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lim G, Wang S, Zhang Y, Tian Y, Mao J. Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents. J Clin Invest. 2009;119(2):295–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tian Y, Wang S, Ma Y, Lim G, Kim H, Mao J. Leptin enhances NMDA-induced spinal excitation in rats: a functional link between adipocytokine and neuropathic pain. Pain. 2011;152(6):1263–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fu R, Han F, Liu L, Yu F, Gui Z, Wang X, Li B, Fang B, Xia L. The effects of leptin on the proliferation and differentiation of primary chondrocytes in vitro and cartilage regeneration in vivo. ACS Biomater Sci Eng. 2019;5(4):1907–19.

    Article  CAS  PubMed  Google Scholar 

  26. Li X, Liu X, Wang Y, Cao F, Chen Z, Hu Z, Yu B, Feng H, Ba Z, Liu T, Li H, Jiang B, Huang Y, Li L, Wu D. Intervertebral disc degeneration in mice with type II diabetes induced by leptin receptor defificiency. BMC Musculoskelet Disord. 2020;21(1):77.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Polyzos SA, Mantzoros CS. Leptin in health and disease: facts and expectations at its twentieth anniversary. Metab. 2015;64(1):5–12.

    Article  CAS  Google Scholar 

  28. Paiva ES, Andretta A, Batista ED, Lobo MMMT, Miranda RC, Nisihara R, Schieferdecker MEM, Boguszewski CL. Serum levels of leptin and adiponectin and clinical parameters in women with fibromyalgia and overweight/obesity. Arch Endocrinol Metab. 2017;61(3):249–56.

    Article  PubMed  Google Scholar 

  29. Münzberg H, Morrison CD. Structure, production, and signaling of leptin. Metab. 2015;64(1):13–23.

    Article  Google Scholar 

  30. Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function, and metabolism. Metab. 2015;64(1):24–34.

    Article  CAS  Google Scholar 

  31. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 1996;387:113–6.

    Article  CAS  PubMed  Google Scholar 

  32. Elmquist JK, Bjørbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol. 1998;395:535–47.

    Article  CAS  PubMed  Google Scholar 

  33. Guo M, Huang T-Y, Garza JC, Chua SC, Lu X-Y. Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours. Int J Neuropsychopharmacol. 2013;16:857–67.

    Article  CAS  PubMed  Google Scholar 

  34. Cordeiro RC, Chaves Filho AJM, Gomes NS, Tomaz VS, Medeiros CD, Queiroz AIG, Maes M, Macedo DS, Carvalho AF. Leptin prevents lipopolysaccharide-induced depressive-like behaviors in mice: involvement of dopamine receptors. Front Psychiatry. 2019;10:125.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant. Proc Natl Acad Sci USA. 2006;103:1593–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Garza JC, Guo M, Zhang W, Lu X-Y. Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling. Mol Psychiatry. 2012;17:790–808.

    Article  CAS  PubMed  Google Scholar 

  37. Roseberry AG, Painter T, Mark GP, Williams JT. Decreased vesicular somatodendritic dopamine stores in leptin-deficient mice. J Neurosci. 2007;27:7021–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G. Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis. 2010;19(4):1155–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Matarese G, Carrieri PB, Montella S, De Rosa V, La Cava A. Leptin as a metabolic link to multiple sclerosis. Nat Rev Neurol. 2010;6:455–61.

    Article  CAS  PubMed  Google Scholar 

  40. Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T, Yin XM, Chen J. Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem. 2007;282:34479–91.

    Article  CAS  PubMed  Google Scholar 

  41. Ong WY, Stohler CS, Herr DR. Role of the prefrontal cortex in pain processing. Mol Neurobiol. 2019;56(2):1137–66.

    Article  CAS  PubMed  Google Scholar 

  42. Dobek CE, Beynon ME, Bosma RL, Stroman PW. Music modulation of pain perception and pain-related activity in the brain, brain stem, and spinal cord: a functional magnetic resonance imaging study. J Pain. 2014;15(10):1057–68.

    Article  PubMed  Google Scholar 

  43. Ruscheweyh R, Deppe M, Lohmann H, et al. Pain is associated with regional grey matter reduction in the general population. Pain. 2011;152(4):904–11.

    Article  PubMed  Google Scholar 

  44. Ceko M, Shir Y, Ouellet JA, Ware MA, Stone LS, Seminowicz DA. Partial recovery of the abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment. Hum Brain Mapp. 2015;36(6):2075–92.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Von Borell E, Langbein J, Després G, Hansen S, Leterrier C, Marchant-Forde J, Marchant-Forde R, Minero M, Mohr E, Prunier A, Valance D, Visser I. Heart rate variability as a measure of autonomic regulation of cardiac activity for assessing stress and welfare in farm animals-a review. Physiol Behav. 2007;92(3):293–316.

    Article  Google Scholar 

  46. Mitterschiffthaler MT, Fu CH, Dalton JA, Andrew CM, Williams SC. A functional MRI study of happy and sad affective states induced by classical music. Hum Brain Mapp. 2007;28(11):1150–62.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Liu X, Xie Z, Li S, He J, Cao S, Xiao Z. PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus. Int J Biol Sci. 2021;17(14):4005–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Angioli R, De Cicco Nardone C, Plotti F, Cafà EV, Dugo N, Damiani P, Ricciardi R, Linciano F, Terranova C. Use of music to reduce anxiety during office hysteroscopy: prospective randomized trial. J Minim Invasive Gynecol. 2014;21(3):454–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Pain Management Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

    Yingying Lv, Junzhen Wu, Yongming Xu, Shaofeng Pu, Chen Li & Dongping Du

Authors
  1. Yingying Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junzhen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yongming Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shaofeng Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dongping Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YingYing Lv and DongPing Du contributed to the conception of the study. YingYing Lv and JunZhen Wu performed the experiment. YingYing Lv, ShaoFeng Pu and Chen Li performed the data analyses. YongMing Xu and JunZhen Wu helped perform the analysis with constructive discussions. YingYing Lv wrote the manuscript. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Dongping Du.

Ethics declarations

Ethics approval and consent to participate

All experimental protocols were approved by the Animal Care and Use Committee of Shanghai Sixth People’s Hospital affiliated with Shanghai Jiao Tong University (ethics certificate number:20160226) and performed as per the National Institutes of Health guidelines for the Care and Use of Laboratory Animals.

Consent for publication

Not applicable.

Competing interests

We declare that we have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lv, Y., Wu, J., Xu, Y. et al. Musical therapy attenuates neuroma pain by modifying leptin expression. BMC Complement Med Ther 22, 316 (2022). https://doi.org/10.1186/s12906-022-03795-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12906-022-03795-8

Keywords

  • Neuroma pain
  • Musical stimulation
  • Leptin

BMC Complementary Medicine and Therapies

ISSN: 2662-7671

Contact us