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Neuronal Transforming Growth Factor beta Signaling via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis.
Gastroenterology. 2018 06; 154(8):2252-2265.e2.G

Abstract

BACKGROUND & AIMS

Chronic pancreatitis (CP) is characterized by pancreatic inflammation and fibrosis, associated with increased pancreatic expression of transforming growth factor beta (TGFB). It is not clear how these might contribute to pain. We investigated whether TGFB signaling via SMAD induces sensitization of pancreatic sensory neurons to increase nociception.

METHODS

CP was induced in Sprague-Dawley rats by infusion of trinitrobenzene sulfonic acid; some rats were given intrathecal infusions of TGFB1. CP was induced in control mice by administration of cerulein; we also studied β1glo/Ptf1acre-ER mice, which on induction overexpress TGFB1 in pancreatic acinar cells, and TGFBr1f/f-CGRPcreER mice, which have inducible disruption of TGFBr1 in calcitonin gene-related peptide-positive neurons. Dominant negative forms of human TGFBR2 and SMAD3 were overexpressed from viral vectors in rat pancreas. Some rats were given the SMAD3 inhibitors SIS3 or halofuginone. After induction of CP, mice were analyzed for pain in behavior tests or electrophysiologic studies of sensory neurons. Pancreatic nociceptor excitability was examined by patch-clamp techniques and nociception was measured by Von Frey Filament tests for referred somatic hyperalgesia and behavioral responses to pancreatic electrical stimulation. Pancreata were collected from mice and rats and analyzed histologically and by enzyme-linked immunosorbent assay and immunohistochemistry.

RESULTS

Overexpression of TGFB in pancreatic acinar cells of mice and infusion of TGFB1 into rats resulted in sensory neuron hyperexcitability, SMAD3 activation, and increased nociception. This was accompanied by a reduction in the transient A-type current in pancreas-specific sensory neurons in rats, a characteristic of nociceptive sensitization in animal models of CP. Conversely, pancreata from TGFBr1f/f-CGRPcreER mice, rats with pancreatic expression of dominant negative forms of human TGFBR2 or SMAD3, and rats given small molecule inhibitors of SMAD3 had attenuated neuronal sensitization and pain behavior following induction of CP. In contrast to findings from peripheral administration of TGFB1, intrathecal infusion of TGFB1 reduced hyperalgesia in rats with CP.

CONCLUSIONS

In pancreata of mice and rats, TGFB promotes peripheral nociceptive sensitization via a direct effect on primary sensory neurons mediated by intra-neuronal SMAD3. This is distinct from the central nervous system, where TGFB reduces nociception. These results provide an explanation for the link between fibrosis and pain in patients with CP. This signaling pathway might be targeted therapeutically to reduce pain in patients with CP.

Authors+Show Affiliations

Johns Hopkins Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.Johns Hopkins Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.Johns Hopkins Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.Johns Hopkins Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ppasric1@jhmi.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29505748

Citation

Liu, Liansheng, et al. "Neuronal Transforming Growth Factor Beta Signaling Via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis." Gastroenterology, vol. 154, no. 8, 2018, pp. 2252-2265.e2.
Liu L, Zhu Y, Noë M, et al. Neuronal Transforming Growth Factor beta Signaling via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis. Gastroenterology. 2018;154(8):2252-2265.e2.
Liu, L., Zhu, Y., Noë, M., Li, Q., & Pasricha, P. J. (2018). Neuronal Transforming Growth Factor beta Signaling via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis. Gastroenterology, 154(8), 2252-e2. https://doi.org/10.1053/j.gastro.2018.02.030
Liu L, et al. Neuronal Transforming Growth Factor Beta Signaling Via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis. Gastroenterology. 2018;154(8):2252-2265.e2. PubMed PMID: 29505748.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuronal Transforming Growth Factor beta Signaling via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis. AU - Liu,Liansheng, AU - Zhu,Yaohui, AU - Noë,Michaël, AU - Li,Qian, AU - Pasricha,Pankaj Jay, Y1 - 2018/03/02/ PY - 2017/07/06/received PY - 2018/02/15/revised PY - 2018/02/26/accepted PY - 2018/3/6/pubmed PY - 2018/7/19/medline PY - 2018/3/6/entrez KW - Mouse Model KW - Neurobiology KW - Pain Signal Transduction KW - Pancreas SP - 2252 EP - 2265.e2 JF - Gastroenterology JO - Gastroenterology VL - 154 IS - 8 N2 - BACKGROUND & AIMS: Chronic pancreatitis (CP) is characterized by pancreatic inflammation and fibrosis, associated with increased pancreatic expression of transforming growth factor beta (TGFB). It is not clear how these might contribute to pain. We investigated whether TGFB signaling via SMAD induces sensitization of pancreatic sensory neurons to increase nociception. METHODS: CP was induced in Sprague-Dawley rats by infusion of trinitrobenzene sulfonic acid; some rats were given intrathecal infusions of TGFB1. CP was induced in control mice by administration of cerulein; we also studied β1glo/Ptf1acre-ER mice, which on induction overexpress TGFB1 in pancreatic acinar cells, and TGFBr1f/f-CGRPcreER mice, which have inducible disruption of TGFBr1 in calcitonin gene-related peptide-positive neurons. Dominant negative forms of human TGFBR2 and SMAD3 were overexpressed from viral vectors in rat pancreas. Some rats were given the SMAD3 inhibitors SIS3 or halofuginone. After induction of CP, mice were analyzed for pain in behavior tests or electrophysiologic studies of sensory neurons. Pancreatic nociceptor excitability was examined by patch-clamp techniques and nociception was measured by Von Frey Filament tests for referred somatic hyperalgesia and behavioral responses to pancreatic electrical stimulation. Pancreata were collected from mice and rats and analyzed histologically and by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Overexpression of TGFB in pancreatic acinar cells of mice and infusion of TGFB1 into rats resulted in sensory neuron hyperexcitability, SMAD3 activation, and increased nociception. This was accompanied by a reduction in the transient A-type current in pancreas-specific sensory neurons in rats, a characteristic of nociceptive sensitization in animal models of CP. Conversely, pancreata from TGFBr1f/f-CGRPcreER mice, rats with pancreatic expression of dominant negative forms of human TGFBR2 or SMAD3, and rats given small molecule inhibitors of SMAD3 had attenuated neuronal sensitization and pain behavior following induction of CP. In contrast to findings from peripheral administration of TGFB1, intrathecal infusion of TGFB1 reduced hyperalgesia in rats with CP. CONCLUSIONS: In pancreata of mice and rats, TGFB promotes peripheral nociceptive sensitization via a direct effect on primary sensory neurons mediated by intra-neuronal SMAD3. This is distinct from the central nervous system, where TGFB reduces nociception. These results provide an explanation for the link between fibrosis and pain in patients with CP. This signaling pathway might be targeted therapeutically to reduce pain in patients with CP. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/29505748/Neuronal_Transforming_Growth_Factor_beta_Signaling_via_SMAD3_Contributes_to_Pain_in_Animal_Models_of_Chronic_Pancreatitis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(18)30247-6 DB - PRIME DP - Unbound Medicine ER -