title: GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex.
abstract: Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC's relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABAAreceptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABAAsignaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABAA-mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator.
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors: R
authors: R
authors: Kaushal
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors: B K
authors: BK
authors: Taylor
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors: A B
authors: AB
authors: Jamal
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors: L
authors: L
authors: Zhang
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors: F
authors: F
authors: Ma
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States.
authors: R
authors: R
authors: Donahue
authors: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0298, United States. Electronic address: kwhigh2@uky.edu.
authors: K N
authors: KN
authors: Westlund
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D005157:Facial Pain / Q000188:drug therapy / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D010075:Oxathiins / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D061221:Trigeminal Nerve Injuries / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D051700:Activating Transcription Factor 3; D000317:Adrenergic alpha-Antagonists; C497108:Atf3 protein, rat; D058787:GABA-A Receptor Antagonists; D010075:Oxathiins; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011963:Receptors, GABA-A; C050877:benoxathian; D019329:Idazoxan; D001640:Bicuculline
keywords: CCI-ION; anti-DβH-saporin; chronic orofacial neuropathic pain; dopamine-beta-hydroxylase; mechanical allodynia; spinal trigeminal caudalis