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

R. Kaushal, B. K. Taylor, A. B. Jamal, L. Zhang, F. Ma, R. Donahue, K. N. Westlund

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 GABAA receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABAA signaling 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.

Original languageEnglish (US)
Pages (from-to)148-159
Number of pages12
StatePublished - Oct 15 2016

Bibliographical note

Funding Information:
These studies were supported by VA Merit Award BX002695 (to KNW) and NIH NINDS funding as R01NS062306 and R01NS045954 (to BKT), NS 039041 (to KNW), and University of Kentucky Wethington Awards (to KNW). Author contributions are as follows: RK performed the surgeries, saporin microinjections, behavioral studies, data analysis, prepared some of the figures, and wrote the first draft of the manuscript. JAB did behavioral studies for the saporin experiments. LZ did behavior testing for the drug studies, data analysis, prepared the figures, and edited the manuscript. FM did behavior testing for the drug studies. RD assisted and provided support and training for the saporin microinjection studies. BKT and KWH designed the study and edited the manuscript and figures. The authors thank Dr. Sabrina McIlwrath for the statistical analysis and graphing.

Publisher Copyright:
© 2016


  • anti-DβH-saporin
  • chronic orofacial neuropathic pain
  • dopamine-beta-hydroxylase
  • mechanical allodynia
  • spinal trigeminal caudalis


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