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

Abstract

Diffuse noxious inhibitory controls (DNIC) is a pain inhibits pain phenomenon demonstrated in humans and animals. DNIC 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 hindpaws 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 (WDR) neuronal activity was evaluated before and during noxious ear pinch, whilst stimulating the ipsilateral paw with von Frey hairs of increased bending force. In both assays, the DNIC response was significantly diminished in the ipsilateral (i.e., injured) paw of SNL animals. However, behavioral loss of DNIC was not observed on the contralateral (i.e., uninjured) paw. Systemic application of nor-Binaltorphimine (nor-BNI), a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-BNI 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 RCeA to promote diminished DNIC following neuropathy.

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

“…We focused on KOR to explore the amygdala-spinal cord connection because KOR in the amygdala have been linked to aversiveness, anxiety and stress responses [38,[51][52][53][54] as well as to averse-affective behaviors in stress-or injury-induced pain conditions [16,[55][56][57]. KOR is expressed in the CeA at particularly high levels [58].…”

“…We studied KOR function in the right CeA because of evidence for right-hemispheric lateralization of CeA function [49,64,65] and KOR function in the CeA related to pain modulation [16,56,57,66]. For example, blockade of KOR in the right, but not left, CeA restored diffuse noxious inhibitory control (DNIC), a measure of descending pain control [56,57].…”

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

“…Descending noradrenergic pathways remain intact after nerve injury but are hypoactive (Hirschberg et al., ; Hughes, Hickey, Hulse, Lumb, & Pickering, ; Patel, Qu, Xie, Porreca, & Dickenson, ), and DNIC are restored following spinal delivery of a noradrenaline reuptake inhibitor (Bannister et al., ). Chronic pain states can also be associated with increased descending facilitation, largely mediated via spinal 5‐HT 2A and 5‐HT 3 receptors (Patel & Dickenson, ; Suzuki, Rahman, Hunt, & Dickenson, ), and enhanced excitatory drive can mask inhibitory signalling (Bannister et al., ; Nation et al., ; Okada‐Ogawa, Porreca, & Meng, ; Phelps, Navratilova, Dickenson, Porreca, & Bannister, ).…”

Central Nervous System Targets: Supraspinal Mechanisms of Analgesia

“…Brainstem MOR involvement is highly likely [25,26]. In chronicity, enhanced descending facilitation from the brain to the spinal cord are proposed mediated, in part, by KOR signaling from the right CeA that promotes diminished DNIC [27]. DNIC are also dysfunctional following sustained morphine treatment in healthy rats, where inactivation of the RVM reinstates DNIC [28].…”