Dopaminergic Inhibition of Pyramidal Cells in Anterior Cingulate Cortex is Defective in Chronic Neuropathic Pain

Chronic neuropathic pain is estimated to affect 3%-4.5% of the worldwide population. It is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders such as depression and anxiety, and disruption of family and social life. Current medical therapeutics often fail to adequately treat chronic neuropathic pain. Deep brain stimulation (DBS) targeting subcortical structures such as the periaqueductal gray, the ventral posterior lateral and medial thalamic nuclei, and the internal capsule has been investigated for the relief of refractory neuropathic pain over the past 3 decades. Recent work has identified the dorsal anterior cingulate cortex (dACC) as a new potential neuromodulation target given its central role in cognitive and affective processing. In this review, the authors briefly discuss the history of DBS for chronic neuropathic pain in the United States and present evidence supporting dACC DBS for this indication. They review existent literature on dACC DBS and summarize important findings from imaging and neurophysiological studies supporting a central role for the dACC in the processing of chronic neuropathic pain. The available neurophysiological and empirical clinical evidence suggests that dACC DBS is a viable therapeutic option for the treatment of chronic neuropathic pain and warrants further investigation.

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Decreased dopaminergic inhibition of pyramidal neurons in anterior cingulate cortex maintains chronic neuropathic pain

Cell Reports ◽

10.1016/j.celrep.2021.109933 ◽

2021 ◽

Vol 37 (9) ◽

pp. 109933

Author(s):

Kevin Lançon ◽

Chaoling Qu ◽

Edita Navratilova ◽

Frank Porreca ◽

Philippe Séguéla

Keyword(s):

Neuropathic Pain ◽

Anterior Cingulate Cortex ◽

Pyramidal Neurons ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Chronic Neuropathic Pain

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The Role of miR-539 in the Anterior Cingulate Cortex in Chronic Neuropathic Pain

Pain Medicine ◽

10.1093/pm/pnx004 ◽

2017 ◽

Vol 18 (12) ◽

pp. 2433-2442 ◽

Cited By ~ 12

Author(s):

Mingxia Ding ◽

Weihong Shen ◽

Yifeng Hu

Keyword(s):

Neuropathic Pain ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Chronic Neuropathic Pain

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GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness

Brain ◽

10.1093/brain/awz203 ◽

2019 ◽

Vol 142 (9) ◽

pp. 2655-2669 ◽

Cited By ~ 2

Author(s):

Dina L Juarez-Salinas ◽

Joao M Braz ◽

Alexander Etlin ◽

Steven Gee ◽

Vikaas Sohal ◽

...

Keyword(s):

Neuropathic Pain ◽

Anterior Cingulate Cortex ◽

Pyramidal Cells ◽

Cingulate Cortex ◽

Inhibitory Interneuron ◽

Anterior Cingulate ◽

Gaba A ◽

Ongoing Pain ◽

Rostral Anterior Cingulate Cortex ◽

Posterior Anterior

Abstract Dysfunction of inhibitory circuits in the rostral anterior cingulate cortex underlies the affective (aversive), but not the sensory-discriminative features (hypersensitivity) of the pain experience. To restore inhibitory controls, we transplanted inhibitory interneuron progenitor cells into the rostral anterior cingulate cortex in a chemotherapy-induced neuropathic pain model. The transplants integrated, exerted a GABA-A mediated inhibition of host pyramidal cells and blocked gabapentin preference (i.e. relieved ongoing pain) in a conditioned place preference paradigm. Surprisingly, pain aversiveness persisted when the transplants populated both the rostral and posterior anterior cingulate cortex. We conclude that selective and long lasting inhibition of the rostral anterior cingulate cortex, in the mouse, has a profound pain relieving effect against nerve injury-induced neuropathic pain. However, the interplay between the rostral and posterior anterior cingulate cortices must be considered when examining circuits that influence ongoing pain and pain aversiveness.

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The Increased In Vivo Firing of Pyramidal Cells But not Interneurons in the Anterior Cingulate Cortex After Neuropathic Pain

10.21203/rs.3.rs-1141019/v1 ◽

2021 ◽

Author(s):

Da-Yu Zhu ◽

Ting-Ting Cao ◽

Hong-Wei Fan ◽

Ming-Zhe Zhang ◽

Hao-Kai Duan ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Firing Rate ◽

Anterior Cingulate Cortex ◽

Pyramidal Cells ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

High Frequency Stimulation ◽

Nociceptive Information

Abstract Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which is further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.

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Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity

Neurology ◽

10.1212/wnl.0000000000006293 ◽

2018 ◽

Vol 91 (14) ◽

pp. e1285-e1294 ◽

Cited By ~ 14

Author(s):

Libat Weizman ◽

Lior Dayan ◽

Silviu Brill ◽

Hadas Nahman-Averbuch ◽

Talma Hendler ◽

...

Keyword(s):

Neuropathic Pain ◽

Graph Theory ◽

Functional Connectivity ◽

Anterior Cingulate Cortex ◽

Sensorimotor Cortex ◽

Controlled Trial ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Emotional Modulation ◽

Chronic Neuropathic Pain

ObjectiveTo characterize the functional brain changes involved in δ-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain.MethodsFifteen patients with chronic radicular neuropathic pain participated in a randomized, double-blind, placebo-controlled trial employing a counterbalanced, within-subjects design. Pain assessments and functional resting state brain scans were performed at baseline and after sublingual THC administration. We examined functional connectivity of the anterior cingulate cortex (ACC) and pain-related network dynamics using graph theory measures.ResultsTHC significantly reduced patients' pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction.ConclusionThese results suggest that the ACC and DLPFC, 2 major cognitive-emotional modulation areas, and their connections to somatosensory areas, are functionally involved in the analgesic effect of THC in chronic pain. This effect may therefore be mediated through induction of functional disconnection between regulatory high-order affective regions and the sensorimotor cortex. Moreover, baseline functional connectivity between these brain areas may serve as a predictor for the extent of pain relief induced by THC.

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Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via Regulation of NMDA Receptor 2B Subunit

Journal of Neuroscience ◽

10.1523/jneurosci.1161-14.2015 ◽

2015 ◽

Vol 35 (1) ◽

pp. 36-52 ◽

Cited By ~ 38

Author(s):

J.-X. Yang ◽

L. Hua ◽

Y.-Q. Li ◽

Y.-Y. Jiang ◽

D. Han ◽

...

Keyword(s):

Neuropathic Pain ◽

Nmda Receptor ◽

Anterior Cingulate Cortex ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Chronic Neuropathic Pain ◽

Caveolin 1

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Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

Communications Biology ◽

10.1038/s42003-021-02188-w ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Bastiaan van der Veen ◽

Sampath K. T. Kapanaiah ◽

Kasyoka Kilonzo ◽

Peter Steele-Perkins ◽

Martin M. Jendryka ◽

...

Keyword(s):

Gene Expression ◽

Anterior Cingulate Cortex ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Pyramidal Neurons ◽

Treatment Options ◽

Pyramidal Cells ◽

Cingulate Cortex ◽

Cell Types ◽

Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

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