Acute Effects of Transforming Growth Factor-β1 on Neuronal Excitability and Involvement in the Pain of Rats with Chronic Pancreatitis

Overview

Journal J Neurogastroenterol Motil

Date 2015 Dec 10

PMID 26645248

Citations 12

Authors

Xiaoyu Zhang

Hang Zheng

Hong-Yan Zhu

Shufen Hu

Shusheng Wang

Xinghong Jiang

Guang-Yin Xu

Affiliations

Soon will be listed here.

Abstract

Background/aims: This study was to investigate whether transforming growth factor-β1 (TGF-β1) plays a role in hyperalgesia in chronic pancreatitis (CP) and the underlying mechanisms.

Methods: CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Dil dye injected into the pancreas was used to label pancreas-specific dorsal root ganglion (DRG) neurons. Whole cell patch clamp recordings and calcium imaging were performed to examine the effect of TGF-β1 on acutely isolated pancreas-specific DRG neurons. Western blot analysis was carried out to measure the expression of TGF-β1 and its receptors.

Results: TNBS injection significantly upregulated expression of TGF-β1 in the pancreas and DRGs, and TGF-β1 receptors in DRGs (T9-T13)in CP rats. Intrathecal injection of TGF-β receptor I antagonist SB431542 attenuated abdominal hyperalgesia in CP rats. TGF-β1 application depolarized the membrane potential and caused firing activity of DRG neurons. TGF-β1 application also reduced rheobase, hyperpolarized action potential threshold, and increased numbers of action potentials evoked by current injection of pancreas-specific DRG neurons. TGF-β1 application also increased the concentration of intracellular calcium of DRG neurons, which was inhibited by SB431542. Furthermore, intrathecal injection of TGF-β1 produced abdominal hyperalgesia in healthy rats.

Conclusions: These results suggest that TGF-β1 enhances neuronal excitability and increases the concentration of intracellular calcium. TGF-β1 and its receptors are involved in abdominal hyperalgesia in CP. This and future study might identify a potentially novel target for the treatment of abdominal pain in CP.

Citing Articles

Recent advances in the understanding and management of chronic pancreatitis pain.

Walker J, Babyok O, Saloman J, Evans Phillips A J Pancreatol. 2024; 7(1):35-44.

PMID: 38524856 PMC: 10959534. DOI: 10.1097/JP9.0000000000000163.

Serum Biomarkers of Nociceptive and Neuropathic Pain in Chronic Pancreatitis.

Saloman J, Li Y, Stello K, Li W, Li S, Evans Phillips A J Pain. 2023; 24(12):2199-2210.

PMID: 37451493 PMC: 10787046. DOI: 10.1016/j.jpain.2023.07.006.

The Antinociceptive Effect of Sympathetic Block is Mediated by Transforming Growth Factor β in a Mouse Model of Radiculopathy.

Luckemeyer D, Xie W, Prudente A, Qualls K, Tonello R, Strong J Neurosci Bull. 2023; 39(9):1363-1374.

PMID: 37165177 PMC: 10465463. DOI: 10.1007/s12264-023-01062-5.

Transcriptional profiles of TGF-β superfamily members in the lumbar DRGs and the effects of activins A and C on inflammatory pain in rats.

Zhang F, Wang B, Hu H, Zhang Y, Chen H, Jiang Z J Physiol Biochem. 2023; 79(2):313-325.

PMID: 36696051 DOI: 10.1007/s13105-022-00943-z.

Telocytes' Role in Modulating Gut Motility Function and Development: Medical Hypotheses and Literature Review.

Banciu D, Cretoiu D, Cretoiu S, Banciu A, Popa D, David R Int J Mol Sci. 2022; 23(13).

PMID: 35806023 PMC: 9267102. DOI: 10.3390/ijms23137017.

References

Bottner M, Krieglstein K, Unsicker K . The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions. J Neurochem. 2000; 75(6):2227-40. DOI: 10.1046/j.1471-4159.2000.0752227.x. View

Xu G, Shenoy M, Winston J, Mittal S, Pasricha P . P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut. 2008; 57(9):1230-7. DOI: 10.1136/gut.2007.134221. View

Inman G, Nicolas F, Callahan J, Harling J, Gaster L, Reith A . SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2002; 62(1):65-74. DOI: 10.1124/mol.62.1.65. View

Kihara Y, Tashiro M, Nakamura H, Yamaguchi T, Yoshikawa H, Otsuki M . Role of TGF-beta1, extracellular matrix, and matrix metalloproteinase in the healing process of the pancreas after induction of acute necrotizing pancreatitis using arginine in rats. Pancreas. 2001; 23(3):288-95. DOI: 10.1097/00006676-200110000-00010. View

Kumazawa T . The polymodal receptor: bio-warning and defense system. Prog Brain Res. 1996; 113:3-18. DOI: 10.1016/s0079-6123(08)61078-x. View

Hu J, Song Z, Zhang H, Qin X, Hu S, Jiang X . Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes. J Neurogastroenterol Motil. 2015; 22(1):129-40. PMC: 4699730. DOI: 10.5056/jnm15091. View

Du X, Hao H, Gigout S, Huang D, Yang Y, Li L . Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission. Pain. 2014; 155(11):2306-22. PMC: 4247381. DOI: 10.1016/j.pain.2014.08.025. View

Feng X, Zhou Y, Meng X, Qi F, Chen W, Jiang X . Hydrogen sulfide increases excitability through suppression of sustained potassium channel currents of rat trigeminal ganglion neurons. Mol Pain. 2013; 9:4. PMC: 3599800. DOI: 10.1186/1744-8069-9-4. View

Wang J, Yu J, Ding C, Han S, Zeng X, Wang J . Transforming growth factor-beta in the red nucleus plays antinociceptive effect under physiological and pathological pain conditions. Neuroscience. 2015; 291:37-45. DOI: 10.1016/j.neuroscience.2015.01.059. View

10.

Xu Q, Zhang X, Duan K, Gu X, Han M, Liu B . Peripheral TGF-β1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents. J Neurosci. 2013; 33(49):19099-111. PMC: 6618781. DOI: 10.1523/JNEUROSCI.4852-12.2013. View

11.

Zhu Y, Colak T, Shenoy M, Liu L, Mehta K, Pai R . Transforming growth factor beta induces sensory neuronal hyperexcitability, and contributes to pancreatic pain and hyperalgesia in rats with chronic pancreatitis. Mol Pain. 2012; 8:65. PMC: 3515355. DOI: 10.1186/1744-8069-8-65. View

12.

Su S, Motoo Y, Xie M, Miyazono K, Sawabu N . Expression of transforming growth factor-beta in spontaneous chronic pancreatitis in the WBN/Kob rat. Dig Dis Sci. 2000; 45(1):151-9. DOI: 10.1023/a:1005481931793. View

13.

Basbaum A, Woolf C . Pain. Curr Biol. 1999; 9(12):R429-31. DOI: 10.1016/s0960-9822(99)80273-5. View

14.

Van Laethem J, Deviere J, Resibois A, Rickaert F, Vertongen P, Ohtani H . Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology. 1995; 108(6):1873-81. DOI: 10.1016/0016-5085(95)90152-3. View

15.

Kang J, Liu C, Derynck R . New regulatory mechanisms of TGF-beta receptor function. Trends Cell Biol. 2009; 19(8):385-94. DOI: 10.1016/j.tcb.2009.05.008. View

16.

Echeverry S, Shi X, Haw A, Liu H, Zhang Z, Zhang J . Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain. 2009; 5:16. PMC: 2669449. DOI: 10.1186/1744-8069-5-16. View

17.

Warshaw A, Banks P, Fernandez-Del Castillo C . AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology. 1998; 115(3):765-76. DOI: 10.1016/s0016-5085(98)70157-x. View

18.

Miao X, Meng X, Wu G, Ju Z, Zhang H, Hu S . Upregulation of cystathionine-β-synthetase expression contributes to inflammatory pain in rat temporomandibular joint. Mol Pain. 2014; 10:9. PMC: 3917612. DOI: 10.1186/1744-8069-10-9. View

19.

Utreras E, Prochazkova M, Terse A, Gross J, Keller J, Iadarola M . TGF-β1 sensitizes TRPV1 through Cdk5 signaling in odontoblast-like cells. Mol Pain. 2013; 9:24. PMC: 3680294. DOI: 10.1186/1744-8069-9-24. View

20.

Cheng J, Ji R . Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008; 33(10):1970-8. PMC: 2570619. DOI: 10.1007/s11064-008-9711-z. View