Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat
Authors: Scott J Thompson
M Catherine Bushnell
Mark H Pitcher
Dale O Kiesewetter
Petra Schweinhardt
Farid Tarum
Gang Niu
Xiaoyuan Chen
Laura S Stone
Journal: Pain (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: opioid system; chronic pain; PET studies; opioid receptors; neuropathy
Affiliations: Division of Intramural Research, National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD, United States., Faculty of Dentistry, McGill University, Montreal, QC, Canada., Division of Intramural Research, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, United States.

Abstract:  The opioid system plays a critical role in both the experience and management of pain. Although acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in patients with chronic pain but are unable to (1) determine whether these changes are due to the chronic pain itself or due to preexisting or medication-induced differences in the endogenous opioid system, and (2) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [F]-FDPN-PET in either sham rats (n = 17) or spared nerve injury rats (n = 17), we confirmed reduced opioid receptor availability in the insula, caudate-putamen, and motor cortex of nerve injured rats 3 months after surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in the caudate-putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate-putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human patients with chronic pain may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression. 

Retracted: No

PubPeer comments:
 There are duplicate immunohistochemistry images. Specifically, Fig. 5C,  Posterior Insula image illustrating mu-opioid receptor imaging is the exact same image in Fig. 6B rotated 90deg., cropped and re-labeled as  Caudate-putamen (CPu) . Importantly, the main conclusion of this paper is that chronic pain reduces opioid receptor availability in the insula, however, only histology images for one group are shown, and it is not labeled or mentioned in the text which group these images represent,![](http: ) either uninjured Sham or injured SNI. ![file] , 
 Thank you for the comment! You are correct that the MOR1 immunochemistry image in Figure 5C also appears as a figure legend in Figure 6B. While the axis legend for Figure 6B was for illustrative purposes only (similar to the other axis labels in Figure 6 depicting a rat on the PET scanner or a rat with water bottles), we incorrectly selected an image from the posterior insula rather than the caudate putamen. As such, we have audited the histology slides to assure that all regions are defined correctly and reaffirm our quantitative results. In terms of the second part of your comment, we agree that the images shown in Figure 5 were not labeled as sham or SNI in the figure legend. While we could have included this information in the legend, we do not feel that it would improve the quality of the data, analysis or results in any way. Again, these images were for illustrative purposes only, and neither the reviewers nor the journal editors requested any changes to the figures or figure legends. Thank you for pointing out these observations! ,