Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats

www.nature.com/scientificreports Correction: Publisher Correction and Correction: Publisher Correction OPEN Received: 8 May 2017 Accepted: 1 August 2017 Published: 19 August 2017 Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats Geehoon Chung 1,2, Chae Young Kim1,3, Yeong-Chan Yun1, Sang Ho Yoon1,3, Myoung-Hwan Kim1,3, Yu Kyeong Kim4 & Sang Jeong Kim 1,2,3,5 Patients with chronic pain easily accompany the negative mood symptoms such as depression and anxiety, and these disturbances in turn affect the aversive perception of pain. However, the underlying mechanisms are largely unknown. We hypothesized that the alteration of metabotropic glutamate receptor 5 (mGluR5) in the brain region underlies such a comorbidity of aversive states. We scanned the brain of chronic neuropathic pain model rats using positron emission tomography (PET) technique with an mGluR5-selective radiotracer [11C] ABP688 and found various brain regions with higher or lower level of mGluR5 compared to control rats. Among the brain areas, a prominent upregulation of mGluR5 was shown in the prelimbic region (PrL) of the medial prefrontal cortex (mPFC) of chronic neuropathic pain animals. A pharmacological blockade of upregulated mGluR5 in the PrL ameliorated the negative symptoms including tactile hypersensitivity and depressive-like behavior, which relieved the subjects from the unpleasant state of chronic neuropathic pain condition. Conversely, lentiviral overexpression of the mGluR5 in the PrL of naïve rats successfully induced comorbid pain and negative moods. Our data provide deeper insight into the shared mechanism of pain perception and negative emotions, identifying a therapeutic target for the treatment of chronic pain and mood disorders. Neuropathic pain persists even after the healing phase following an injury and patients suffer from symptoms including allodynia, hyperalgesia, and spontaneous pain. Central sensitization mechanisms of the pain system including the spinal cord and the brain are considered to be the main reason of such an unrelenting chronic pain. As the pain goes chronic, supraspinal brain centers become crucial for how the patients perceive pain. Previous studies have demonstrated that the long-term pain arising from peripheral nerve injury induces maladaptive changes in the various cortical structures1–6 including the prefrontal cortex (PFC) which are also involved in the affective and emotional processing of the brain. Chronic neuropathic pain patients easily accompany the abnormal mental states such as depression or anxiety7–9, and these emotional mood symptoms in return affect the manifestation of the sensory pain symptoms10–13. This indicates that the shared supraspinal brain mechanisms play a critical role in the pathologically amplified negative perception in chronic pain condition. One possible candidate is the alteration of metabotropic glutamate receptor 5 (mGluR5) in the brain. The mGluR5 is a G protein-coupled receptor which plays an important role in the modulation of neuronal excitability and is involved in the pathophysiology of various neurological and psychiatric disorders. The changes of mGluR5 expression in the brain regions and their functional impact have been reported from studies of chronic pain14–16 and negative mood disorders17–19. Both of pain processing and mental disorders are modulated by mGluR5 actions, 1 Department of Physiology, Seoul National University College of Medicine, Seoul, Korea. 2Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Korea. 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. 4Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea. 5Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. Geehoon Chung and Chae Young Kim contributed equally to this work. Correspondence and requests for materials should be addressed to S.J. (email: ) SCIeNtIfIC Reports | 7:9743 | DOI:10.1038/s41598-017-09991-8 1 www.nature.com/scientificreports/ Figure 1. Experimental design and assessment of mGluR5 level in the brain. (A) After the surgery, SNL group animals showed reduced hindpaw withdrawal threshold compared to control group (n = 10 per each group, ***p < 0.001, Two-way repeated measures ANOVA with Bonferroni test). (B) Experimental design of [11C] ABP688 PET scan and sample image. PET scan was performed to animal 15–24 days after the SNL or sham surgery. (C) Time-activity curve of [11C] ABP688 in the cerebellum. The cerebellum was used as a reference region for the quantification of the mGluR5, as this region is devoid of the mGluR5. (D) Averaged [11C] ABP688 images from each group. The images without proportional scaling were used. The anterior-posterior (AP), mediolateral (ML), dorsoventral (DV) coordinates in the representative plane images are the distance from the bregma (mm). implicating change of this receptor in the brain circuit as their common mechanisms. In the processing of pain and negative mood, the affective and cognitive interactions actively participate in the perception, and the maladaptive sensitization of this system in chronic pain condition amplifies negative appraisal and aversive sensations20–22. Our primary hypothesis is that the persistent unavoidable pain would trigger the alteration of mGluR5 in the brain area related to the negative appraisal such as the PFC, and this alteration, in turn, mediates pain facilitation and precipitates negative mood. In this study, we sought to identify the brain alteration underlying the comorbidity of chronic pain and negative mood disorders. We used the mGluR5 as a target molecule, as this molecule is known to be involved in the pathophysiology of pain as well as negative moods. The common brain circuit was pursued by investigating the altered mGluR5 in the chronic pain state and was verified by effects of the local mGluR5 manipulation on the pain and mood behaviors. To assess the regional expression of mGluR5 among brains of chronic neuropathic pain rats and control rats, positron emission tomography (PET) technique was used with [11C] ABP688, a highly selective radiotracer of mGluR5. After this step, we went on further tests with pharmacological modulation and viral manipulation of mGluR5 in the identified brain area to investigate the specific role of the local mGluR5 alteration in the pain-related and mood-related behaviors. Results Altered mGluR5 level in the brain following nerve injury-induced neuropathic pain. Right L5 spinal nerve ligation (SNL) surgery-performed rats were used for chronic neuropathic pain group23 and sham surgery-performed rats were used for the control group. After surgery, paw withdrawal threshold was measured using von Frey test and SNL rats showed a consistent reduc (...truncated)