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5GABAA receptors">α5GABAA receptors play a pronociceptive role and avoid the rate-dependent depression of the Hoffmann reflex in diabetic neuropathic pain and reduce primary afferent excitability

Hernández-Reyes, José E.a; Salinas-Abarca, Ana B.b; Vidal-Cantú, Guadalupe C.b; Raya-Tafolla, Guadalupea; Elias-Viñas, Davidc; Granados-Soto, Viniciob; Delgado-Lezama, Rodolfoa,*

doi: 10.1097/j.pain.0000000000001515
Research Paper
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Diabetic neuropathy is an incapacitating complication in diabetic patients. The cellular and molecular mechanisms involved in this pathology are poorly understood. Previous studies have suggested that the loss of spinal GABAergic inhibition participate in painful diabetic neuropathy. However, the role of extrasynaptic α5 subunit-containing GABAA5GABAA) receptors in this process is not known. The purpose of this study was to investigate the role of 5GABAA receptors">α5GABAA receptors in diabetes-induced tactile allodynia, loss of rate-dependent depression (RDD) of the Hoffmann reflex (HR), and modulation of primary afferent excitability. Intraperitoneal administration of streptozotocin induced tactile allodynia. Intrathecal injection of α5GABAA receptor inverse agonist, L-655,708, produced tactile allodynia in naive rats, whereas it reduced allodynia in diabetic rats. In healthy rats, electrical stimulation of the tibial nerve at 5 Hz induced RDD of the HR, although intrathecal treatment with L-655,708 (15 nmol) abolished RDD of the HR. Streptozotocin induced the loss of RDD of the HR, while intrathecal L-655,708 (15 nmol) restored RDD of the HR. L-655,708 (15 nmol) increased tonic excitability of the primary afferents without affecting the phasic excitability produced by the primary afferent depolarization. 5GABAA receptors">α5GABAA receptors were immunolocalized in superficial laminae of the dorsal horn and L4 to L6 dorsal root ganglion. Streptozotocin increased mean fluorescence intensity and percentage of neurons expressing 5GABAA receptors">α5GABAA receptors in dorsal horn and L4 to L6 dorsal root ganglia in 10-week diabetic rats. Our results suggest that spinal 5GABAA receptors">α5GABAA receptors modulate the HR, play an antinociceptive and pronociceptive role in healthy and diabetic rats, respectively, and are tonically active in primary afferents.

5GABAA receptors">α5GABAA receptors modulate the Hoffmann reflex, play an antinociceptive and pronociceptive role in healthy and diabetic rats, respectively, and are tonically active in primary afferents.

aDepartamento de Fisiología, Biofísica y Neurociencias, Cinvestav, Mexico City, Mexico

bNeurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, Sede Sur, Mexico City, Mexico

cDepartamento de Ingeniería Eléctrica, Cinvestav, Mexico City, Mexico

Corresponding author. Address: Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav, Unidad Zacatenco Av. IPN 2508, Col. San Pedro Zacatenco, Mexico City 07300, Mexico. Tel.: +52 55 5747 38 00. E-mail address: rdelgado@fisio.cinvestav.mx (R. Delgado-Lezama).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received November 26, 2018

Received in revised form January 11, 2019

Accepted January 25, 2019

© 2019 International Association for the Study of Pain
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