Neural correlates of hyperalgesia in the monosodium iodoacetate model of osteoarthritis pain

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Abstract

Background

The mechanisms driving osteoarthritic pain remain poorly understood, but there is increasing evidence for a role of the central nervous system in the chronification of pain. We used functional magnetic resonance imaging to investigate the influence of a model of unilateral knee osteoarthritis on nociceptive processing.

Results

Four to five weeks post intra-articular injection of monosodium iodoacetate (MIA, 1 mg) into the left knee, Sprague Dawley rats were anesthetized for functional magnetic resonance imaging studies to characterize the neural response to a noxious stimulus (intra-articular capsaicin injection). In a two-arm cross-over design, 5 µM/50 µl capsaicin was injected into either the left knee ( n = 8, CAPS-MIA) or right control knee ( n = 8, CAPS-CON), preceded by contralateral vehicle (SAL) injection. To assess neural correlates of mechanical hyperalgesia, hindpaws were stimulated with von Frey hairs (8 g: MIA; 15 g: control knee, based on behavioral withdrawal responses). The CAPS-MIA group exhibited significant activation of the periaqueductal gray, unilateral thalamus and bilateral mensencephalon, superior-colliculus, and hippocampus, with no significant activation in the other groups/conditions. Capsaicin injection increased functional connectivity in the mid-brain network and mediodorsal thalamic nucleus, hippocampus, and globus pallidus, which was significantly stronger in CAPS-MIA compared to CAPS-CON groups. Mechanical stimulation of the hyperalgesic (ipsilateral to MIA knee) and normalgesic (contralateral) hindpaws evoked qualitatively different brain activation with more widespread brainstem and anterior cingulate (ACC) activation when stimulating the hyperalgesic paw, and clearer frontal sensory activation from the normalgesic paw.

Conclusions

We provide evidence for modulation of nociceptive processing in a chronic knee osteoarthritis pain model with stronger brain activation and alteration of brain networks induced by the pro-nociceptive stimulus. We also report a shift to a medial pain activation pattern following stimulation of the hyperalgesic hindpaw. Taken together, our data support altered neural pain processing as a result of peripheral and central pain sensitization in this model.

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Most cited references 21

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A meta-analysis of 140 neuroimaging studies was performed using the activation-likelihood-estimate (ALE) method to explore the location and extent of activation in the brain in response to noxious stimuli in healthy volunteers. The first analysis involved the creation of a likelihood map illustrating brain activation common across studies using noxious stimuli. The left thalamus, right anterior cingulate cortex (ACC), bilateral anterior insulae, and left dorsal posterior insula had the highest likelihood of being activated. The second analysis contrasted noxious cold with noxious heat stimulation and revealed higher likelihood of activation to noxious cold in the subgenual ACC and the amygdala. The third analysis assessed the implications of using either a warm stimulus or a resting baseline as the control condition to reveal activation attributed to noxious heat. Comparing noxious heat to warm stimulation led to peak ALE values that were restricted to cortical regions with known nociceptive input. The fourth analysis tested for a hemispheric dominance in pain processing and showed the importance of the right hemisphere, with the strongest ALE peaks and clusters found in the right insula and ACC. The fifth analysis compared noxious muscle with cutaneous stimuli and the former type was more likely to evoke activation in the posterior and anterior cingulate cortices, precuneus, dorsolateral prefrontal cortex, and cerebellum. In general, results indicate that some brain regions such as the thalamus, insula and ACC have a significant likelihood of activation regardless of the type of noxious stimuli, while other brain regions show a stimulus-specific likelihood of being activated. Copyright © 2011 Wiley Periodicals, Inc.

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Functional neuroimaging studies have shown that experimentally induced acute pain is processed within at least 2 parallel networks of brain structures collectively known as the pain matrix. The relevance of this finding to clinical pain is not known, because no direct comparisons of experimental and clinical pain have been performed in the same group of patients. The aim of this study was to compare directly the brain areas involved in processing arthritic pain and experimental pain in a group of patients with osteoarthritis (OA). Twelve patients with knee OA underwent positron emission tomography of the brain, using (18)F-fluorodeoxyglucose (FDG). Scanning was performed during 3 different pain states: arthritic knee pain, experimental knee pain, and pain-free. Significant differences in the neuronal uptake of FDG between different pain states were investigated using statistical parametric mapping software. Both pain conditions activated the pain matrix, but arthritic pain was associated with increased activity in the cingulate cortex, the thalamus, and the amygdala; these areas are involved in the processing of fear, emotions, and in aversive conditioning. Our results suggest that studies of experimental pain provide a relevant but quantitatively incomplete picture of brain activity during arthritic pain. The search for new analgesics for arthritis that act on the brain should focus on drugs that modify this circuitry.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Pain

Journal ID (iso-abbrev): Mol Pain

Journal ID (publisher-id): MPX

Journal ID (hwp): spmpx

Title: Molecular Pain

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Electronic): 1744-8069

Publication date (Electronic): 11 April 2016

Publication date Collection: 2016

Volume: 12

Electronic Location Identifier: 1744806916642445

Affiliations

[1 ]Radiological Sciences, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK

[2 ]Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK

[3 ]School of Life Sciences, University of Nottingham, Nottingham, UK

[4 ]Medical Imaging Unit, School of Medicine, University of Nottingham, Nottingham, UK

Author notes

[*]Victoria Chapman, Arthritis Research UK Pain Centre, School of Life Sciences, Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK. Email: Victoria.chapman@ 123456nottingham.ac.uk Dorothee Auer, Arthritis Research UK Pain Centre, Radiological Sciences, Division of Clinical Neuroscience, B Floor West Block, Queen’s Medical Centre, Nottingham NG7 2UH, UK. Email: Dorothee.Auer@ 123456nottingham.ac.uk

Article

Publisher ID: 10.1177_1744806916642445

DOI: 10.1177/1744806916642445

PMC ID: 4956384

PubMed ID: 27068285

SO-VID: 8b70dcf3-95c6-407f-840a-eba1c6f116b3

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 12 January 2016

Date revision received : 24 February 2016

Date accepted : 7 March 2016

Custom metadata

cover-date January-December 2016

ScienceOpen disciplines: Molecular medicine

Keywords: hyperalgesia,pain fmri,osteoarthritis model

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: hyperalgesia, pain fmri, osteoarthritis model

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