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Location, Location, Location?

Location, Location, Location? COMMENTARY Is the Pain of Diabetic Neuropathy Generated by Hyperactive Sensory Neurons? Nigel A. Calcutt reasonable assumption that pain is generated at the site where it is perceived to emanate from. The last is perhaps ain is a useful sensation. Nociceptive pain pro- most controversial, as it implies a form of phantom pain vides warning of impending or actual tissue dam- (7). The recent study by Orestes et al. (8) adds support to age and prompts aversive or attentive actions that the hypothesis that peripheral sensory neurons are hy- Pprotect the body from harm. People who do not perexcitable during diabetes. Previous studies have iden- feel pain, due to mutation of certain ion channels (1), tified changes in expression of assorted ion channels that suffer a lifetime of otherwise avoidable injuries. The con- are involved with action potential generation or sculpting sequences of losing the ability to feel pain also are high- in diabetic rodents and the idea that altered membrane lighted by the symptoms and clinical outcomes of diabetic depolarization properties could generate allodynia, hyper- neuropathy. Sensory neuropathy, in conjunction with vas- algesia, or spontaneous pain is not new. Fewer have cular disease and impaired wound healing, leads to un- addressed the mechanisms by which diabetes might pro- attended lesions and ulcers, infection, and amputation (2). mote such changes. A particular appeal of the present However, despite having a predominant neuropathy phe- work lies in the evidence that inappropriate glycosylation notype of degeneration and sensory loss, a proportion of of an ion channel, in this case the Ca 3.2 isoform of the people with diabetes also report spontaneous tingling, T-type calcium channel, produces a posttranslation modi- pricking, and pain sensations (3). This neuropathic pain is fication that enhances function, thereby offering a simple an enigmatic and disruptive symptom that adds psycho- pathogenic mechanism that is directly related to poor logical insult to the physical injury of progressive nerve glycemic control. degeneration. The prevalence of neuropathic pain is fre- The argument presented by Orestes et al. is grounded quently underestimated, but a recent community-based in studies that manipulate glycosylation of Ca 3.2, when study found that pain was reported by a third of all par- expressed in human embryonic kidney cells, to establish that ticipants (4). There are currently only three FDA-approved Ca 3.2 function can be modulated by glycosylation status, as treatments for painful diabetic neuropathy: the anticon- reported for other ion channels (9). Pertinence to sensory vulsant pregabalin, the serotonin–norepinephrine reuptake neurons is then demonstrated, as enhanced T-type calcium inhibitor (SNRI) duloxetine, and the opioid/SNRI tapentadol. currents found in sensory neurons obtained from the ob/ob All are used to treat diverse pain conditions, are likely to mouse model of type 2 diabetes are ablated by the deglyco- suppress pain perception rather than intervene in patho- sylation agent neuraminidase. Finally, relevance of these in genic mechanisms of painful diabetic neuropathy, and vitro studies to abnormal pain perception is suggested by have undesirable side effects. None are effective in more showing that injection of neuraminidase to the paws of ob/ob than an unpredictable subset of diabetic patients and they mice rapidly ameliorates mechanical and thermal hyper- do not dramatically outperform the historical off-label use algesia. These assays measure behavioral indices of stimulus- of tricyclic antidepressants (5). Treating painful diabetic evoked nociceptive pain (10), not the spontaneous pain neuropathy therefore remains a march through a list of experienced by many diabetic patients, but there are clinical potential treatments in search of an acceptable balance parallels in disorders identified during quantitative sensory between pain relief and side effects (6). testing (11). The progression from idealized cell biology to Data emerging from animal models of painful diabetic animal model of disease makes this study a substantive ad- neuropathy advances three broad mechanisms of pain dition to the literature. Together with the recent identifica- generation: inappropriate or exaggerated activity of pe- tion of the glucose derivative methylglyoxal as another ripheral sensory neurons, distortion of sensory processing molecule that posttranslationally modifies ions channels within the spinal cord, and spontaneous activity in the (12), these data implicate hyperglycemia-initiated periph- central nervous system that is perceived as pain deriving eral sensory drive as a primary pathogenic mechanism of from the periphery (Fig. 1). Of these, the first reflects the painful diabetic neuropathy. A notable absence from the work of Orestes et al. is direct demonstration that Ca 3.2 undergoes abnormal From the Department of Pathology, University of California, San Diego, La glycosylation in diabetic animals, and it remains plausible Jolla, California. that alleviation of hyperalgesia is mediated by other actions Corresponding author: Nigel A. Calcutt, ncalcutt@ucsd.edu. DOI: 10.2337/db13-1158 of neuraminidase in vivo. The extent to which sensory 2013 by the American Diabetes Association. Readers may use this article as neuron hyperexcitability drives hyperalgesia or spontane- long as the work is properly cited, the use is educational and not for profit, ous pain in diabetes also deserves consideration. While it and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. is known that gain of function modifications to ion chan- See accompanying original article, p. 3828. nels can lead to pain-associated behaviors in animals that 3658 DIABETES, VOL. 62, NOVEMBER 2013 diabetes.diabetesjournals.org N.A. CALCUTT FIG. 1. The location of potential generator and amplifier sites for neuropathic pain in diabetes includes peripheral sensory neurons, the spinal cord, and the brain. have direct human equivalents (13), diabetes-induced pain benefit from the emerging promise of personalized frequently coexists with the degenerative neuropathy medicine. phenotype of reduced production, transport, and stimulus- evoked spinal release of neurotransmitters (14). A hyper- ACKNOWLEDGMENTS excitable peripheral sensory neuron with no voice will No potential conflicts of interest relevant to this article likely remain silent—although perhaps causing higher or- were reported. der neurons to adjust their listening mechanisms. The iden- tification of ion channel glycosylation as a driving force for REFERENCES pain must also be reconciled with preclinical evidence that 1. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes impaired insulin signaling rather than hyperglycemia pro- congenital inability to experience pain. Nature 2006;444:894–898 motes hyperalgesia (15) and the efficacy of interventions 2. Boulton AJ. Diabetic neuropathy: is pain God’s greatest gift to mankind? that prevent onset of hyperalgesia without altering hyper- Semin Vasc Surg 2012;25:61–65 glycemia (16). Clinical studies emphasize that acute hy- 3. Koroschetz J, Rehm SE, Gockel U, et al. Fibromyalgia and neuropathic perglycemia does not alter perception of sensory stimuli or pain—differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol 2011;11:55 pain (17,18) whereas, paradoxically, restoring normogly- 4. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and cemia in diabetic patients can initiate the pain state com- characteristics of painful diabetic neuropathy in a large community-based monly called insulin neuritis (19). diabetic population in the U.K. Diabetes Care 2011;34:2220–2224 Peripheral hyperexcitability is an appealing mechanism 5. Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. that may contribute to pain in some diabetic patients and Randomized double-blind study comparing the efficacy of gabapentin with offers a therapeutic approach targeting glycosylated ion amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999;159:1931–1937 channels that may quickly alleviate pain, with improving 6. Bril V, England J, Franklin GM, et al.; American Academy of Neurology; glycemic control presumably being the preferred long- American Association of Neuromuscular and Electrodiagnostic Medicine; term goal. However, the diverse manifestations of painful American Academy of Physical Medicine and Rehabilitation. Evidence- diabetic neuropathy and variable responses to current drug based guideline: treatment of painful diabetic neuropathy: report of the interventions imply that a number of mechanisms can American Academy of Neurology, the American Association of Neuro- contribute, with each patient having a specific pathogenic muscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [published correction appears in profile. New clinical tests or biomarkers to identify the lo- Neurology 2011;77:603]. Neurology 2011;76:1758–1765 cation of pain generation or amplification sites and specific 7. Rajbhandari SM, Jarratt JA, Griffiths PD, Ward JD. Diabetic neuropathic pathogenic mechanisms would be valuable tools in guiding pain in a leg amputated 44 years previously. Pain 1999;83:627–629 choice of therapy. The complexity of painful diabetic neu- 8. Orestes P, Osuru HP, McIntire WE, et al. Reversal of neuropathic pain in ropathy may not be solved for all by a single intervention, diabetes by targeting glycosylation of Ca 3.2 T-type calcium channels. making this condition a plausible archetype that could Diabetes 2013;62:3828–3838 diabetes.diabetesjournals.org DIABETES, VOL. 62, NOVEMBER 2013 3659 COMMENTARY 9. Tyrrell L, Renganathan M, Dib-Hajj SD, Waxman SG. Glycosylation alters 14. Malmberg AB, O’Connor WT, Glennon JC, Ceseña R, Calcutt NA. Impaired steady-state inactivation of sodium channel Nav1.9/NaN in dorsal root formalin-evoked changes of spinal amino acid levels in diabetic rats. Brain ganglion neurons and is developmentally regulated. J Neurosci 2001;21: Res 2006;1115:48–53 9629–9637 15. Romanovsky D, Cruz NF, Dienel GA, Dobretsov M. Mechanical hyper- 10. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Phar- algesia correlates with insulin deficiency in normoglycemic streptozotocin- macol Rev 2001;53:597–652 treated rats. Neurobiol Dis 2006;24:384–394 11. Baron R, Tölle TR, Gockel U, Brosz M, Freynhagen R. A cross-sectional 16. Calcutt NA, Freshwater JD, Mizisin AP. Prevention of sensory disorders in cohort survey in 2100 patients with painful diabetic neuropathy and diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment postherpetic neuralgia: differences in demographic data and sensory with ciliary neurotrophic factor. Diabetologia 2004;47:718–724 symptoms. Pain 2009;146:34–40 17. Chan AW, MacFarlane IA, Bowsher D. Short term fluctuations in blood 12. Bierhaus A, Fleming T, Stoyanov S, et al. Methylglyoxal modification of glucose concentrations do not alter pain perception in diabetic-patients with Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in and without painful peripheral neuropathy. Diabetes Res 1990;14:15–19 diabetic neuropathy [published correction appears in Nat Med 2012;18: 18. Frøkjaer JB, Søfteland E, Graversen C, Dimcevski G, Drewes AM. Effect of 1445]. Nat Med 2012;18:926–933 acute hyperglycaemia on sensory processing in diabetic autonomic neu- 13. Klein CJ, Wu Y, Kilfoyle DH, et al. Infrequent SCN9A mutations in con- ropathy. Eur J Clin Invest 2010;40:883–886 genital insensitivity to pain and erythromelalgia. J Neurol Neurosurg 19. Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: a re- Psychiatry 2013;84:386–391 versible painful autonomic neuropathy. Ann Neurol 2010;67:534–541 3660 DIABETES, VOL. 62, NOVEMBER 2013 diabetes.diabetesjournals.org http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetes Pubmed Central

Location, Location, Location?

Diabetes , Volume 62 (11) – Oct 18, 2013

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References (24)

Publisher
Pubmed Central
Copyright
© 2013 by the American Diabetes Association.
ISSN
0012-1797
eISSN
1939-327X
DOI
10.2337/db13-1158
Publisher site
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Abstract

COMMENTARY Is the Pain of Diabetic Neuropathy Generated by Hyperactive Sensory Neurons? Nigel A. Calcutt reasonable assumption that pain is generated at the site where it is perceived to emanate from. The last is perhaps ain is a useful sensation. Nociceptive pain pro- most controversial, as it implies a form of phantom pain vides warning of impending or actual tissue dam- (7). The recent study by Orestes et al. (8) adds support to age and prompts aversive or attentive actions that the hypothesis that peripheral sensory neurons are hy- Pprotect the body from harm. People who do not perexcitable during diabetes. Previous studies have iden- feel pain, due to mutation of certain ion channels (1), tified changes in expression of assorted ion channels that suffer a lifetime of otherwise avoidable injuries. The con- are involved with action potential generation or sculpting sequences of losing the ability to feel pain also are high- in diabetic rodents and the idea that altered membrane lighted by the symptoms and clinical outcomes of diabetic depolarization properties could generate allodynia, hyper- neuropathy. Sensory neuropathy, in conjunction with vas- algesia, or spontaneous pain is not new. Fewer have cular disease and impaired wound healing, leads to un- addressed the mechanisms by which diabetes might pro- attended lesions and ulcers, infection, and amputation (2). mote such changes. A particular appeal of the present However, despite having a predominant neuropathy phe- work lies in the evidence that inappropriate glycosylation notype of degeneration and sensory loss, a proportion of of an ion channel, in this case the Ca 3.2 isoform of the people with diabetes also report spontaneous tingling, T-type calcium channel, produces a posttranslation modi- pricking, and pain sensations (3). This neuropathic pain is fication that enhances function, thereby offering a simple an enigmatic and disruptive symptom that adds psycho- pathogenic mechanism that is directly related to poor logical insult to the physical injury of progressive nerve glycemic control. degeneration. The prevalence of neuropathic pain is fre- The argument presented by Orestes et al. is grounded quently underestimated, but a recent community-based in studies that manipulate glycosylation of Ca 3.2, when study found that pain was reported by a third of all par- expressed in human embryonic kidney cells, to establish that ticipants (4). There are currently only three FDA-approved Ca 3.2 function can be modulated by glycosylation status, as treatments for painful diabetic neuropathy: the anticon- reported for other ion channels (9). Pertinence to sensory vulsant pregabalin, the serotonin–norepinephrine reuptake neurons is then demonstrated, as enhanced T-type calcium inhibitor (SNRI) duloxetine, and the opioid/SNRI tapentadol. currents found in sensory neurons obtained from the ob/ob All are used to treat diverse pain conditions, are likely to mouse model of type 2 diabetes are ablated by the deglyco- suppress pain perception rather than intervene in patho- sylation agent neuraminidase. Finally, relevance of these in genic mechanisms of painful diabetic neuropathy, and vitro studies to abnormal pain perception is suggested by have undesirable side effects. None are effective in more showing that injection of neuraminidase to the paws of ob/ob than an unpredictable subset of diabetic patients and they mice rapidly ameliorates mechanical and thermal hyper- do not dramatically outperform the historical off-label use algesia. These assays measure behavioral indices of stimulus- of tricyclic antidepressants (5). Treating painful diabetic evoked nociceptive pain (10), not the spontaneous pain neuropathy therefore remains a march through a list of experienced by many diabetic patients, but there are clinical potential treatments in search of an acceptable balance parallels in disorders identified during quantitative sensory between pain relief and side effects (6). testing (11). The progression from idealized cell biology to Data emerging from animal models of painful diabetic animal model of disease makes this study a substantive ad- neuropathy advances three broad mechanisms of pain dition to the literature. Together with the recent identifica- generation: inappropriate or exaggerated activity of pe- tion of the glucose derivative methylglyoxal as another ripheral sensory neurons, distortion of sensory processing molecule that posttranslationally modifies ions channels within the spinal cord, and spontaneous activity in the (12), these data implicate hyperglycemia-initiated periph- central nervous system that is perceived as pain deriving eral sensory drive as a primary pathogenic mechanism of from the periphery (Fig. 1). Of these, the first reflects the painful diabetic neuropathy. A notable absence from the work of Orestes et al. is direct demonstration that Ca 3.2 undergoes abnormal From the Department of Pathology, University of California, San Diego, La glycosylation in diabetic animals, and it remains plausible Jolla, California. that alleviation of hyperalgesia is mediated by other actions Corresponding author: Nigel A. Calcutt, ncalcutt@ucsd.edu. DOI: 10.2337/db13-1158 of neuraminidase in vivo. The extent to which sensory 2013 by the American Diabetes Association. Readers may use this article as neuron hyperexcitability drives hyperalgesia or spontane- long as the work is properly cited, the use is educational and not for profit, ous pain in diabetes also deserves consideration. While it and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. is known that gain of function modifications to ion chan- See accompanying original article, p. 3828. nels can lead to pain-associated behaviors in animals that 3658 DIABETES, VOL. 62, NOVEMBER 2013 diabetes.diabetesjournals.org N.A. CALCUTT FIG. 1. The location of potential generator and amplifier sites for neuropathic pain in diabetes includes peripheral sensory neurons, the spinal cord, and the brain. have direct human equivalents (13), diabetes-induced pain benefit from the emerging promise of personalized frequently coexists with the degenerative neuropathy medicine. phenotype of reduced production, transport, and stimulus- evoked spinal release of neurotransmitters (14). A hyper- ACKNOWLEDGMENTS excitable peripheral sensory neuron with no voice will No potential conflicts of interest relevant to this article likely remain silent—although perhaps causing higher or- were reported. der neurons to adjust their listening mechanisms. The iden- tification of ion channel glycosylation as a driving force for REFERENCES pain must also be reconciled with preclinical evidence that 1. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes impaired insulin signaling rather than hyperglycemia pro- congenital inability to experience pain. Nature 2006;444:894–898 motes hyperalgesia (15) and the efficacy of interventions 2. Boulton AJ. Diabetic neuropathy: is pain God’s greatest gift to mankind? that prevent onset of hyperalgesia without altering hyper- Semin Vasc Surg 2012;25:61–65 glycemia (16). Clinical studies emphasize that acute hy- 3. Koroschetz J, Rehm SE, Gockel U, et al. Fibromyalgia and neuropathic perglycemia does not alter perception of sensory stimuli or pain—differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol 2011;11:55 pain (17,18) whereas, paradoxically, restoring normogly- 4. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and cemia in diabetic patients can initiate the pain state com- characteristics of painful diabetic neuropathy in a large community-based monly called insulin neuritis (19). diabetic population in the U.K. Diabetes Care 2011;34:2220–2224 Peripheral hyperexcitability is an appealing mechanism 5. Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. that may contribute to pain in some diabetic patients and Randomized double-blind study comparing the efficacy of gabapentin with offers a therapeutic approach targeting glycosylated ion amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999;159:1931–1937 channels that may quickly alleviate pain, with improving 6. Bril V, England J, Franklin GM, et al.; American Academy of Neurology; glycemic control presumably being the preferred long- American Association of Neuromuscular and Electrodiagnostic Medicine; term goal. However, the diverse manifestations of painful American Academy of Physical Medicine and Rehabilitation. Evidence- diabetic neuropathy and variable responses to current drug based guideline: treatment of painful diabetic neuropathy: report of the interventions imply that a number of mechanisms can American Academy of Neurology, the American Association of Neuro- contribute, with each patient having a specific pathogenic muscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [published correction appears in profile. New clinical tests or biomarkers to identify the lo- Neurology 2011;77:603]. Neurology 2011;76:1758–1765 cation of pain generation or amplification sites and specific 7. Rajbhandari SM, Jarratt JA, Griffiths PD, Ward JD. Diabetic neuropathic pathogenic mechanisms would be valuable tools in guiding pain in a leg amputated 44 years previously. Pain 1999;83:627–629 choice of therapy. The complexity of painful diabetic neu- 8. Orestes P, Osuru HP, McIntire WE, et al. Reversal of neuropathic pain in ropathy may not be solved for all by a single intervention, diabetes by targeting glycosylation of Ca 3.2 T-type calcium channels. making this condition a plausible archetype that could Diabetes 2013;62:3828–3838 diabetes.diabetesjournals.org DIABETES, VOL. 62, NOVEMBER 2013 3659 COMMENTARY 9. Tyrrell L, Renganathan M, Dib-Hajj SD, Waxman SG. Glycosylation alters 14. Malmberg AB, O’Connor WT, Glennon JC, Ceseña R, Calcutt NA. Impaired steady-state inactivation of sodium channel Nav1.9/NaN in dorsal root formalin-evoked changes of spinal amino acid levels in diabetic rats. Brain ganglion neurons and is developmentally regulated. J Neurosci 2001;21: Res 2006;1115:48–53 9629–9637 15. Romanovsky D, Cruz NF, Dienel GA, Dobretsov M. Mechanical hyper- 10. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Phar- algesia correlates with insulin deficiency in normoglycemic streptozotocin- macol Rev 2001;53:597–652 treated rats. Neurobiol Dis 2006;24:384–394 11. Baron R, Tölle TR, Gockel U, Brosz M, Freynhagen R. A cross-sectional 16. Calcutt NA, Freshwater JD, Mizisin AP. Prevention of sensory disorders in cohort survey in 2100 patients with painful diabetic neuropathy and diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment postherpetic neuralgia: differences in demographic data and sensory with ciliary neurotrophic factor. Diabetologia 2004;47:718–724 symptoms. Pain 2009;146:34–40 17. Chan AW, MacFarlane IA, Bowsher D. Short term fluctuations in blood 12. Bierhaus A, Fleming T, Stoyanov S, et al. Methylglyoxal modification of glucose concentrations do not alter pain perception in diabetic-patients with Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in and without painful peripheral neuropathy. Diabetes Res 1990;14:15–19 diabetic neuropathy [published correction appears in Nat Med 2012;18: 18. Frøkjaer JB, Søfteland E, Graversen C, Dimcevski G, Drewes AM. Effect of 1445]. Nat Med 2012;18:926–933 acute hyperglycaemia on sensory processing in diabetic autonomic neu- 13. Klein CJ, Wu Y, Kilfoyle DH, et al. Infrequent SCN9A mutations in con- ropathy. Eur J Clin Invest 2010;40:883–886 genital insensitivity to pain and erythromelalgia. J Neurol Neurosurg 19. Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: a re- Psychiatry 2013;84:386–391 versible painful autonomic neuropathy. Ann Neurol 2010;67:534–541 3660 DIABETES, VOL. 62, NOVEMBER 2013 diabetes.diabetesjournals.org

Journal

DiabetesPubmed Central

Published: Oct 18, 2013

There are no references for this article.