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Kappa opioid signaling in the right central amygdala causes hind paw specific loss of diffuse noxious inhibitory controls in experimental neuropathic pain

Phelps, Caroline E.a; Navratilova, Editaa; Dickenson, Anthony H.b; Porreca, Franka; Bannister, Kirstyc,*

doi: 10.1097/j.pain.0000000000001553
Research Paper
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Diffuse noxious inhibitory controls (DNICs) is a pain-inhibits-pain phenomenon demonstrated in humans and animals. Diffuse noxious inhibitory control is diminished in many chronic pain states, including neuropathic pain. The efficiency of DNIC has been suggested to prospectively predict both the likelihood of pain chronification and treatment response. Little is known as to why DNIC is dysfunctional in neuropathic pain. Here, we evaluated DNIC in the rat L5/L6 spinal nerve ligation (SNL) model of chronic pain using both behavioral and electrophysiological outcomes. For behavior, nociceptive thresholds were determined using response to noxious paw pressure on both hind paws as the test stimulus before, and after, injection of a conditioning stimulus of capsaicin into the left forepaw. Functionally, the spike firing of spinal wide-dynamic-range neuronal activity was evaluated before and during noxious ear pinch, while stimulating the ipsilateral paw with von Frey hairs of increased bending force. In both assays, the DNIC response was significantly diminished in the ipsilateral (ie, injured) paw of SNL animals. However, behavioral loss of DNIC was not observed on the contralateral (ie, uninjured) paw. Systemic application of nor-binaltorphimine, a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-binaltorphimine into the right central amygdala (RCeA) of SNL rats did not affect baseline thresholds but restored DNIC both behaviorally and electrophysiologically. Cumulatively, these data suggest that net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the right central amygdala to promote diminished DNIC after neuropathy.

Net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the RCeA to promote diminished DNIC following neuropathy.

aDepartment of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, United States

bDepartment of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

cDepartment of Pharmacology and Therapeutics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom

Corresponding author. Address: Department of Pharmacology and Therapeutics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, United Kingdom. Tel.: 0207 848 4617. E-mail address: kirsty.bannister@kcl.ac.uk (K. Bannister).

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

Received November 06, 2018

Received in revised form February 27, 2019

Accepted February 28, 2019

© 2019 International Association for the Study of Pain
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