Skip to main content
Top
Published in: Molecular Pain 1/2015

Open Access 01-12-2015 | Research

Impairments of the primary afferent nerves in a rat model of diabetic visceral hyposensitivity

Authors: Li Dong, Xizi Liang, Biying Sun, Xiaowei Ding, Hongxiu Han, Guohua Zhang, Weifang Rong

Published in: Molecular Pain | Issue 1/2015

Login to get access

Abstract

Background

Diabetic neuropathy in visceral organs such as the gastrointestinal (GI) tract is still poorly understood, despite that GI symptoms are among the most common diabetic complications. The present study was designed to explore the changes in visceral sensitivity and the underlying functional and morphological deficits of the sensory nerves in short-term diabetic rats. Here, we compared the colorectal distension (CRD)-induced visceromotor response (VMR, an index of visceral pain) in vivo, the mechanosensitivity of colonic afferents ex vivo as well as the expression of protein gene product (PGP) 9.5 and calcitonin gene-related peptide (CGRP) in colon between diabetic (3–6 weeks after streptozotocin injection) and control (age-matched vehicle injection) rats.

Results

VMR was markedly decreased in the diabetic compared to the control rats. There was a significant decrease in multiunit pelvic afferent nerve responses to ramp distension of the ex vivo colon and single unit analysis indicated that an impaired mechanosensitivity of low-threshold and wide dynamic range fibers may underlie the afferent hyposensitivity in the diabetic colon. Fewer PGP 9.5- or CGRP-immunoreactive fibers and lower protein level of PGP 9.5 were found in the colon of diabetic rats.

Conclusions

These observations revealed the distinctive feature of colonic neuropathy in short-term diabetic rats that is characterized by a diminished sensory innervation and a blunted mechanosensitivity of the remnant sensory nerves.
Literature
1.
go back to reference Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. American Diabetes Association. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–62.CrossRefPubMed Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. American Diabetes Association. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–62.CrossRefPubMed
3.
go back to reference Rayner CK, Verhagen MA, Hebbard GS, DiMatteo AC, Doran SM, Horowitz M. Proximal gastric compliance and perception of distension in type 1 diabetes mellitus: effects of hyperglycemia. Am J Gastroenterol. 2000;95:1175–83.CrossRefPubMed Rayner CK, Verhagen MA, Hebbard GS, DiMatteo AC, Doran SM, Horowitz M. Proximal gastric compliance and perception of distension in type 1 diabetes mellitus: effects of hyperglycemia. Am J Gastroenterol. 2000;95:1175–83.CrossRefPubMed
4.
go back to reference Samsom M, Salet GA, Roelofs JM, Akkermans LM, Vanberge-Henegouwen GP, Smout AJ. Compliance of the proximal stomach and dyspeptic symptoms in patients with type I diabetes mellitus. Dig Dis Sci. 1995;40:2037–42.CrossRefPubMed Samsom M, Salet GA, Roelofs JM, Akkermans LM, Vanberge-Henegouwen GP, Smout AJ. Compliance of the proximal stomach and dyspeptic symptoms in patients with type I diabetes mellitus. Dig Dis Sci. 1995;40:2037–42.CrossRefPubMed
5.
go back to reference Frøkjaer JB, Andersen SD, Ejskaer N, Funch-Jensen P, Arendt-Nielsen L, Gregersen H, et al. Gut sensations in diabetic autonomic neuropathy. Pain. 2007;131:320–9.CrossRefPubMed Frøkjaer JB, Andersen SD, Ejskaer N, Funch-Jensen P, Arendt-Nielsen L, Gregersen H, et al. Gut sensations in diabetic autonomic neuropathy. Pain. 2007;131:320–9.CrossRefPubMed
6.
go back to reference Brock C, Graversen C, Frøkjaer JB, Søfteland E, Valeriani M, Drewes AM. Peripheral and central nervous contribution to gastrointestinal symptoms in diabetic patients with autonomic neuropathy. Eur J Pain. 2013;17:820–31.CrossRefPubMed Brock C, Graversen C, Frøkjaer JB, Søfteland E, Valeriani M, Drewes AM. Peripheral and central nervous contribution to gastrointestinal symptoms in diabetic patients with autonomic neuropathy. Eur J Pain. 2013;17:820–31.CrossRefPubMed
7.
go back to reference Lelic D, Brock C, Simrén M, Frøkjaer JB, Søfteland E, Dimcevski G, et al. The brain networks encoding visceral sensation in patients with gastrointestinal symptoms due to diabetic neuropathy. Neurogastroenterol Motil. 2014;6:46–58.CrossRef Lelic D, Brock C, Simrén M, Frøkjaer JB, Søfteland E, Dimcevski G, et al. The brain networks encoding visceral sensation in patients with gastrointestinal symptoms due to diabetic neuropathy. Neurogastroenterol Motil. 2014;6:46–58.CrossRef
8.
go back to reference Caruana BJ, Wald A, Hinds JP, Eidelman BH. Anorectal sensory and motor function in neurogenic fecal incontinence. Comparison between multiple sclerosis and diabetes mellitus. Gastroenterology. 1991;100:465–70.PubMed Caruana BJ, Wald A, Hinds JP, Eidelman BH. Anorectal sensory and motor function in neurogenic fecal incontinence. Comparison between multiple sclerosis and diabetes mellitus. Gastroenterology. 1991;100:465–70.PubMed
9.
go back to reference Lelic D, Brock C, Søfteland E, Frøkjær JB, Andresen T, Simrén M, et al. Brain networks encoding rectal sensation in type 1 diabetes. Neuroscience. 2013;237:96–105.CrossRefPubMed Lelic D, Brock C, Søfteland E, Frøkjær JB, Andresen T, Simrén M, et al. Brain networks encoding rectal sensation in type 1 diabetes. Neuroscience. 2013;237:96–105.CrossRefPubMed
10.
go back to reference Wald A, Tunuguntla AK. Anorectal sensorimotor dysfunction in fetal incontinence and diabetes mellitus. Modification with biofeedback therapy. N Engl J Med. 1984;310:1282–7.CrossRefPubMed Wald A, Tunuguntla AK. Anorectal sensorimotor dysfunction in fetal incontinence and diabetes mellitus. Modification with biofeedback therapy. N Engl J Med. 1984;310:1282–7.CrossRefPubMed
11.
go back to reference Beyak MJ, Bulmer DC, Sellers D, Grundy D. Impairment of rectal afferent mechanosensitivity in experimental diabetes in the rat. Neurogastroenterol Motil. 2009;21:678–81.CrossRefPubMed Beyak MJ, Bulmer DC, Sellers D, Grundy D. Impairment of rectal afferent mechanosensitivity in experimental diabetes in the rat. Neurogastroenterol Motil. 2009;21:678–81.CrossRefPubMed
12.
go back to reference Grabauskas G, Heldsinger A, Wu X, Xu D, Zhou S, Owyang C. Diabetic visceral hypersensitivity is associated with activation of mitogen-activated kinase in rat dorsal root ganglia. Diabetes. 2011;60:1743–51.PubMedCentralCrossRefPubMed Grabauskas G, Heldsinger A, Wu X, Xu D, Zhou S, Owyang C. Diabetic visceral hypersensitivity is associated with activation of mitogen-activated kinase in rat dorsal root ganglia. Diabetes. 2011;60:1743–51.PubMedCentralCrossRefPubMed
13.
go back to reference Calcutt NA, Freshwater JD, Mizisin AP. Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia. 2004;47:718–24.CrossRefPubMed Calcutt NA, Freshwater JD, Mizisin AP. Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia. 2004;47:718–24.CrossRefPubMed
14.
go back to reference Cao XH, Byun HS, Chen SR, Cai YQ, Pan HL. Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor. J Neurochem. 2010;114:1460–75.PubMedCentralPubMed Cao XH, Byun HS, Chen SR, Cai YQ, Pan HL. Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor. J Neurochem. 2010;114:1460–75.PubMedCentralPubMed
15.
go back to reference Fuchs D, Birklein F, Reeh PW, Sauer SK. Sensitized peripheral nociception in experimental diabetes of the rat. Pain. 2010;151:496–505.CrossRefPubMed Fuchs D, Birklein F, Reeh PW, Sauer SK. Sensitized peripheral nociception in experimental diabetes of the rat. Pain. 2010;151:496–505.CrossRefPubMed
16.
go back to reference Hong S, Morrow TJ, Paulson PE, Isom LL, Wiley JW. Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem. 2004;279:29341–50.PubMedCentralCrossRefPubMed Hong S, Morrow TJ, Paulson PE, Isom LL, Wiley JW. Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem. 2004;279:29341–50.PubMedCentralCrossRefPubMed
17.
go back to reference Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, et al. Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci. 2007;27:3305–16.CrossRefPubMed Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, et al. Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci. 2007;27:3305–16.CrossRefPubMed
18.
go back to reference Li F, Drel VR, Szabó C, Stevens MJ, Obrosova IG. Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. Diabetes. 2005;54:1514–22.CrossRefPubMed Li F, Drel VR, Szabó C, Stevens MJ, Obrosova IG. Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. Diabetes. 2005;54:1514–22.CrossRefPubMed
19.
20.
go back to reference Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics. 2009;6:638–47.CrossRefPubMed Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics. 2009;6:638–47.CrossRefPubMed
21.
go back to reference Romanovsky D, Wang J, Al-Chaer ED, Stimers JR, Dobretsov M. Comparison of metabolic and neuropathy profiles of rats with streptozotocin-induced overt and moderate insulinopenia. Neuroscience. 2010;170:337–47.PubMedCentralCrossRefPubMed Romanovsky D, Wang J, Al-Chaer ED, Stimers JR, Dobretsov M. Comparison of metabolic and neuropathy profiles of rats with streptozotocin-induced overt and moderate insulinopenia. Neuroscience. 2010;170:337–47.PubMedCentralCrossRefPubMed
22.
go back to reference Obrosova IG, Xu W, Lyzogubov VV, Ilnytska O, Mashtalir N, Vareniuk I, et al. PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radic Biol Med. 2008;44:972–81.PubMedCentralCrossRefPubMed Obrosova IG, Xu W, Lyzogubov VV, Ilnytska O, Mashtalir N, Vareniuk I, et al. PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radic Biol Med. 2008;44:972–81.PubMedCentralCrossRefPubMed
23.
go back to reference Christianson JA, Ryals JM, Johnson MS, Dobrowsky RT, Wright DE. Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Neuroscience. 2007;145:303–13.PubMedCentralCrossRefPubMed Christianson JA, Ryals JM, Johnson MS, Dobrowsky RT, Wright DE. Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Neuroscience. 2007;145:303–13.PubMedCentralCrossRefPubMed
24.
go back to reference Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci USA. 2004;101:11094–8.PubMedCentralCrossRefPubMed Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci USA. 2004;101:11094–8.PubMedCentralCrossRefPubMed
25.
go back to reference Chen SL, Wu XY, Cao ZJ, Fan J, Wang M, Owyang C, et al. Subdiaphragmatic vagal afferent nerves modulate visceral pain. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1441–9.PubMedCentralCrossRefPubMed Chen SL, Wu XY, Cao ZJ, Fan J, Wang M, Owyang C, et al. Subdiaphragmatic vagal afferent nerves modulate visceral pain. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1441–9.PubMedCentralCrossRefPubMed
26.
go back to reference Rong W, Hillsley K, Davis JB, Hicks G, Winchester WJ, Grundy D. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J Physiol. 2004;560:867–81.PubMedCentralCrossRefPubMed Rong W, Hillsley K, Davis JB, Hicks G, Winchester WJ, Grundy D. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J Physiol. 2004;560:867–81.PubMedCentralCrossRefPubMed
27.
go back to reference Zhang G, Dmitrieva N, Liu Y, McGinty KA, Berkley KJ. Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat. Am J Physiol Regul Integr Comp Physiol. 2008;294:R162–71.PubMedCentralCrossRefPubMed Zhang G, Dmitrieva N, Liu Y, McGinty KA, Berkley KJ. Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat. Am J Physiol Regul Integr Comp Physiol. 2008;294:R162–71.PubMedCentralCrossRefPubMed
28.
go back to reference Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain. 1998;76:151–7.CrossRefPubMed Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain. 1998;76:151–7.CrossRefPubMed
Metadata
Title
Impairments of the primary afferent nerves in a rat model of diabetic visceral hyposensitivity
Authors
Li Dong
Xizi Liang
Biying Sun
Xiaowei Ding
Hongxiu Han
Guohua Zhang
Weifang Rong
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2015
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/s12990-015-0075-5

Other articles of this Issue 1/2015

Molecular Pain 1/2015 Go to the issue