Sex-related Exacerbation of Injury-induced Mechanical Hypersensitivity in GAD67 Haplodeficient Mice

Overview

Journal Pain

Specialties Neurology
Psychiatry

Date 2023 Aug 14

PMID 37578506

Authors

Aude Charron

Lucie Pepino

Pascale Malapert

Vincent Debrauwer

Francis Castets

Chiara Salio

Aziz Moqrich

Affiliations

Soon will be listed here.

Abstract

Decreased GABA levels in injury-induced loss of spinal inhibition are still under intense interest and debate. Here, we show that GAD67 haplodeficient mice exhibited a prolonged injury-induced mechanical hypersensitivity in postoperative, inflammatory, and neuropathic pain models. In line with this, we found that loss of 1 copy of the GAD67-encoding gene Gad1 causes a significant decrease in GABA contents in spinal GABAergic neuronal profiles. Consequently, GAD67 haplodeficient males and females were unresponsive to the analgesic effect of diazepam. Remarkably, all these phenotypes were more pronounced in GAD67 haplodeficient females. These mice had significantly much lower amount of spinal GABA content, exhibited an exacerbated pain phenotype during the second phase of the formalin test, developed a longer lasting mechanical hypersensitivity in the chronic constriction injury of the sciatic nerve model, and were unresponsive to the pain relief effect of the GABA-transaminase inhibitor phenylethylidenehydrazine. Our study provides strong evidence for a role of GABA levels in the modulation of injury-induced mechanical pain and suggests a potential role of the GABAergic system in the prevalence of some painful diseases among females.

References

Kuba T, Wu H, Nazarian A, Festa E, Barr G, Jenab S . Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats. Horm Behav. 2005; 49(4):441-9. DOI: 10.1016/j.yhbeh.2005.09.007. View

Castro-Lopes J, Tavares I, Coimbra A . GABA decreases in the spinal cord dorsal horn after peripheral neurectomy. Brain Res. 1993; 620(2):287-91. DOI: 10.1016/0006-8993(93)90167-l. View

Kimoto S, Bazmi H, Lewis D . Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268. Am J Psychiatry. 2014; 171(9):969-78. PMC: 4376371. DOI: 10.1176/appi.ajp.2014.14010004. View

Soghomonian J, Martin D . Two isoforms of glutamate decarboxylase: why?. Trends Pharmacol Sci. 1999; 19(12):500-5. DOI: 10.1016/s0165-6147(98)01270-x. View

Boyle K, Gradwell M, Yasaka T, Dickie A, Polgar E, Ganley R . Defining a Spinal Microcircuit that Gates Myelinated Afferent Input: Implications for Tactile Allodynia. Cell Rep. 2019; 28(2):526-540.e6. PMC: 6635381. DOI: 10.1016/j.celrep.2019.06.040. View

Bennett G, Xie Y . A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988; 33(1):87-107. DOI: 10.1016/0304-3959(88)90209-6. View

Yoo S, Santos C, Reynders A, Marics I, Malapert P, Gaillard S . TAFA4 relieves injury-induced mechanical hypersensitivity through LDL receptors and modulation of spinal A-type K current. Cell Rep. 2021; 37(4):109884. DOI: 10.1016/j.celrep.2021.109884. View

Mifflin K, Benson C, Thorburn K, Baker G, Kerr B . Manipulation of Neurotransmitter Levels Has Differential Effects on Formalin-Evoked Nociceptive Behavior in Male and Female Mice. J Pain. 2016; 17(4):483-98. DOI: 10.1016/j.jpain.2015.12.013. View

Todd A . GABA and glycine in synaptic glomeruli of the rat spinal dorsal horn. Eur J Neurosci. 1996; 8(12):2492-8. DOI: 10.1111/j.1460-9568.1996.tb01543.x. View

10.

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

11.

Martin D, Liu H, Martin S, Wu S . Structural features and regulatory properties of the brain glutamate decarboxylases. Neurochem Int. 2000; 37(2-3):111-9. DOI: 10.1016/s0197-0186(00)00014-0. View

12.

Sandkuhler J . Models and mechanisms of hyperalgesia and allodynia. Physiol Rev. 2009; 89(2):707-58. DOI: 10.1152/physrev.00025.2008. View

13.

Ocvirk R, Pearson Murphy B, Franklin K, Abbott F . Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test. Pain. 2008; 138(2):402-409. DOI: 10.1016/j.pain.2008.01.019. View

14.

Wang Y, Kakizaki T, Sakagami H, Saito K, Ebihara S, Kato M . Fluorescent labeling of both GABAergic and glycinergic neurons in vesicular GABA transporter (VGAT)-venus transgenic mouse. Neuroscience. 2009; 164(3):1031-43. DOI: 10.1016/j.neuroscience.2009.09.010. View

15.

Ibuki T, Dunbar S, Yaksh T . Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain. 1997; 70(2-3):125-32. DOI: 10.1016/s0304-3959(96)03283-6. View

16.

Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J, Obata K, Kaneko T . Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003; 467(1):60-79. DOI: 10.1002/cne.10905. View

17.

Eaton M, Plunkett J, Karmally S, Martinez M, Montanez K . Changes in GAD- and GABA- immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. J Chem Neuroanat. 1999; 16(1):57-72. DOI: 10.1016/s0891-0618(98)00062-3. View

18.

Nullmeier S, Elmers C, DHanis W, Sandhu K, Stork O, Yanagawa Y . Glutamic acid decarboxylase 67 haplodeficiency in mice: consequences of postweaning social isolation on behavior and changes in brain neurochemical systems. Brain Struct Funct. 2020; 225(6):1719-1742. PMC: 7321906. DOI: 10.1007/s00429-020-02087-6. View

19.

Mackie M, Hughes D, Maxwell D, Tillakaratne N, Todd A . Distribution and colocalisation of glutamate decarboxylase isoforms in the rat spinal cord. Neuroscience. 2003; 119(2):461-72. DOI: 10.1016/s0306-4522(03)00174-x. View

20.

Polgar E, Hughes D, Arham A, Todd A . Loss of neurons from laminas I-III of the spinal dorsal horn is not required for development of tactile allodynia in the spared nerve injury model of neuropathic pain. J Neurosci. 2005; 25(28):6658-66. PMC: 6725431. DOI: 10.1523/JNEUROSCI.1490-05.2005. View