Allodynia and Hyperalgesia in Diabetic Rats Are Mediated by GABA and Depletion of Spinal Potassium-chloride Co-transporters

Overview

Journal Pain

Specialties Neurology
Psychiatry

Date 2008 Aug 30

PMID 18755547

Citations 65

Authors

Corinne G Jolivalt

Corinne A Lee

Khara M Ramos

Nigel A Calcutt

Affiliations

Soon will be listed here.

Abstract

Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABA(A) receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats, while levels of NKCC1 and the GABA(A) receptor were unchanged. Spinal delivery of the GABA(A) receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABA(A) receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate- dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally mediated hyperalgesia in diabetes.

Citing Articles

Evidence for spinal disinhibition as a pain-generating mechanism in fibromyalgia syndrome.

Marshall A, Burgess J, Goebel A, Frank B, Alam U, Marshall A Pain Rep. 2024; 10(1):e1236.

PMID: 39734431 PMC: 11677609. DOI: 10.1097/PR9.0000000000001236.

Development of KCC2 therapeutics to treat neurological disorders.

Kadam S, Hegarty S Front Mol Neurosci. 2024; 17:1503070.

PMID: 39720463 PMC: 11666659. DOI: 10.3389/fnmol.2024.1503070.

Rate-Dependent Depression of the Hoffmann Reflex: Practical Applications in Painful Diabetic Neuropathy.

Han L, Calcutt N, Zhou X Diabetes Metab J. 2024; 48(6):1029-1046.

PMID: 39610132 PMC: 11621664. DOI: 10.4093/dmj.2024.0614.

Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury in rats.

Pan Y, Talifu Z, Wang X, Ke H, Zhang C, Xu X CNS Neurosci Ther. 2024; 30(9):e70045.

PMID: 39267289 PMC: 11393004. DOI: 10.1111/cns.70045.

Attenuation of Streptozotocin-Induced Diabetic Neuropathic Allodynia by Flavone Derivative Through Modulation of GABA-ergic Mechanisms and Endogenous Biomarkers.

Altaf N, Ur Rehman N, Karim N, Khan I, Ahsan Halim S, Alotaibi B Neurochem Res. 2024; 49(4):980-997.

PMID: 38170385 DOI: 10.1007/s11064-023-04078-5.

References

Mizisin A, DiStefano P, Liu X, Garrett D, Tonra J . Decreased accumulation of endogenous brain-derived neurotrophic factor against constricting sciatic nerve ligatures in streptozotocin-diabetic and galactose-fed rats. Neurosci Lett. 1999; 263(2-3):149-52. DOI: 10.1016/s0304-3940(99)00131-7. View

Hoybergs Y, Meert T . The effect of low-dose insulin on mechanical sensitivity and allodynia in type I diabetes neuropathy. Neurosci Lett. 2007; 417(2):149-54. DOI: 10.1016/j.neulet.2007.02.087. View

Yaksh T . Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain. 1989; 37(1):111-123. DOI: 10.1016/0304-3959(89)90160-7. View

Malmberg A, Yaksh T . Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats. J Neurosci. 1995; 15(4):2768-76. PMC: 6577797. View

Payne J, Rivera C, Voipio J, Kaila K . Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci. 2003; 26(4):199-206. DOI: 10.1016/S0166-2236(03)00068-7. View

Calcutt N, Malmberg A, Yamamoto T, Yaksh T . Tolrestat treatment prevents modification of the formalin test model of prolonged pain in hyperglycemic rats. Pain. 1994; 58(3):413-420. DOI: 10.1016/0304-3959(94)90136-8. View

Freshwater J, Svensson C, Malmberg A, Calcutt N . Elevated spinal cyclooxygenase and prostaglandin release during hyperalgesia in diabetic rats. Diabetes. 2002; 51(7):2249-55. DOI: 10.2337/diabetes.51.7.2249. View

Coull J, Boudreau D, Bachand K, Prescott S, Nault F, Sik A . Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003; 424(6951):938-42. DOI: 10.1038/nature01868. View

Dirig D, Yaksh T . Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model. J Pharmacol Exp Ther. 1995; 275(1):219-27. View

10.

Miletic G, Miletic V . Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn. Pain. 2007; 137(3):532-539. PMC: 2569893. DOI: 10.1016/j.pain.2007.10.016. View

11.

Calcutt N, Chaplan S . Spinal pharmacology of tactile allodynia in diabetic rats. Br J Pharmacol. 1998; 122(7):1478-82. PMC: 1565094. DOI: 10.1038/sj.bjp.0701538. View

12.

Malmberg A, Yaksh T . Pharmacology of the spinal action of ketorolac, morphine, ST-91, U50488H, and L-PIA on the formalin test and an isobolographic analysis of the NSAID interaction. Anesthesiology. 1993; 79(2):270-81. DOI: 10.1097/00000542-199308000-00012. View

13.

Sugimoto K, Murakawa Y, Sima A . Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J Peripher Nerv Syst. 2002; 7(1):44-53. DOI: 10.1046/j.1529-8027.2002.02005.x. View

14.

Gao B, Ziskind-Conhaim L . Development of glycine- and GABA-gated currents in rat spinal motoneurons. J Neurophysiol. 1995; 74(1):113-21. DOI: 10.1152/jn.1995.74.1.113. View

15.

Dickenson A, Chapman V, Green G . The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol. 1997; 28(5):633-8. DOI: 10.1016/s0306-3623(96)00359-x. View

16.

Kaimal S, Gireesh G, Paulose C . Decreased GABAA receptor function in the brain stem during pancreatic regeneration in rats. Neurochem Res. 2007; 32(11):1813-22. DOI: 10.1007/s11064-007-9283-3. View

17.

Sherman S, Loomis C . Morphine insensitive allodynia is produced by intrathecal strychnine in the lightly anesthetized rat. Pain. 1994; 56(1):17-29. DOI: 10.1016/0304-3959(94)90146-5. View

18.

Calcutt N, Freshwater J, Mizisin A . Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia. 2004; 47(4):718-24. DOI: 10.1007/s00125-004-1354-2. View

19.

Hefferan M, Kucharova K, Kinjo K, Kakinohana O, Sekerkova G, Nakamura S . Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity. J Neurosci. 2007; 27(42):11179-91. PMC: 6673044. DOI: 10.1523/JNEUROSCI.0989-07.2007. View

20.

Flemmer A, Gimenez I, Dowd B, Darman R, Forbush B . Activation of the Na-K-Cl cotransporter NKCC1 detected with a phospho-specific antibody. J Biol Chem. 2002; 277(40):37551-8. DOI: 10.1074/jbc.M206294200. View