Pain and dyskinesia in Parkinson's disease may share common pathophysiological mechanisms – An fMRI study

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Highlights

  • Dyskinetic PD patients experience increased pain sensitivity.

  • Centrally sensitized nociceptive pathways resembling levodopa induced sensitization are implicated.

  • This is not directly influenced by dopamine.

Abstract

Background

Parkinson's disease (PD) patients develop levodopa induced dyskinesia with disease progression from sensitization of central pathways. Pain pathways are also impacted with suggestions dyskinetic patients may process pain differently.

Objective

Establish if centrally sensitized nociceptive pathways are altered and dopaminergically driven in dyskinetic patients.

Methods

Clinical characteristics, affect, pain thresholds and sensitivity to pressure stimulation in the ON and OFF medication states as well as distribution of pain related activation of cortical regions on BOLD fMRI were assessed and compared between groups of patients suffering from dyskinesia and not.

Results

Dyskinetic PD participants experienced increased pressure pain sensitivity. This was associated with increased pressure induced pain>innocuous BOLD activity in areas associated with encoding pain intensity, pain spatial orientation, descending pain mediation, sensorimotor integration, and motor control. Levodopa reduced pressure pain ratings and improved negative affect, though did not impact BOLD activity differently between the groups.

Conclusion

Dyskinetic PD patients experience increased pain sensitivity and centrally sensitized nociceptive pathways resembling levodopa induced sensitization though this is not directly influenced by dopamine.

Introduction

Levodopa has revolutionized the treatment of Parkinson's disease (PD) with dramatic and stable symptom amelioration seen in a majority of cases. [1] This benefit however wanes with disease progression with the development of motor complications, namely levodopa induced dyskinesia (LID) and fluctuations. The underlying mechanism is linked to the pulsatile nature of administration and thought to originate from drug induced neural plastic changes, with the LIDs reflecting pharmacological sensitization of motor pathways, and fluctuations an effect of drug tolerance [2,3].

The increased responsiveness of nociceptive neurons to their normal or subthreshold afferent input leading to enhanced pain perception is known as sensitization [4]. Sensitization of the nociceptive system can be triggered by injury to the nervous system and exposure to inflammatory cytokines, drugs [5], and ongoing nociceptive input (e.g. activity-dependent long term potentiation [6,7]. When this occurs in the central nervous system, it is termed central sensitization. The cellular mechanisms for this stem from a trigger inducing the nociceptive neuron to undergo post-translational, transcriptional and translational changes, thus causing changes to channel and receptor function and expression, neurotransmitter generation and release, and structural cell changes. This ultimately leads to altered synaptic strength and aberrant activity. [8] Behavioral manifestations of sensitization include allodynia, hyperalgesia, hyperpathia and hypoalgesia. Pain aberrance and central sensitization in PD are fairly well established and characterized. [9] Psychophysical methods with mechanical and thermal stimulation allow the identification of phenomena such as hyperalgesia and allodynia, which indicate that the pain system has undergone sensitization in a pro-nociceptive manner while functional imaging can objectively demonstrate increased neuronal activity in the central nervous system in association with these psychophysical findings.

The presence of LID is an independent predictor for other non-motor symptoms, such as compulsive behaviors and pain [10], raising the possibility that these symptoms may share similar mechanisms. Specifically, compulsive drug taking is linked to sensitization of the nucleus accumbens on PET scans in dyskinetic patients, demonstrating that levodopa induced plastic changes do indeed affect non-motor pathways [11]. The link with aberrant pain processing in dyskinetic patients is multipronged. A preclinical study has demonstrated hyperalgesia in mice that have been primed with levodopa after drug withdrawal [12]. Persistent pain has been linked to high dopaminergic therapy dosage in Parkinson's patients [13].

Furthermore, dyskinetic PD patients seem to experience large increases in cold pain threshold and tolerance after a dose of levodopa [14] possibly reflecting the presence of dopaminergic nociceptive pathways that have undergone pharmacological sensitisation. Alternate, non-dopaminergic pathways may also be impacted by levodopa in dyskinetic patients with post-mortem, imaging, and preclinical studies [15] suggesting neurotransmitter changes such as enhanced cannabinoid transmission [16], and increased preproenkephalin expression [17]. Despite some evidence suggesting differential central modulation of clinical pain by dopaminergic medication in PD [13,18], no studies have specifically examined this in dyskinetic patients. Brain regions of interest include areas implicated in pain processing (‘pain neuromatrix’) cingulate cortex, the primary and secondary sensory cortices, and the insula [19] and areas mediating anti-nociception such as the pregenual cingulate cortex and nucleus accumbens (NAcc) [20,21]; the ventral tegmental area (VTA) and periaqueductal grey (PAG) [22].

The aim of this study is to firstly establish if central pain processing is altered in dyskinetic PD patients by comparing pain thresholds and changes in pain sensitivity on psychophysical testing, and to establish the distribution of pain related activation of cortical regions. This study then further aims to establish if centrally sensitized nociceptive pathways are dopaminergic in nature with the expectation that if these pathways are sensitized, a more pronounced reduction in pain sensitivity, accompanied by increased pain induced activation in the brain after administration of levodopa in dyskinetic patients would be seen.

Section snippets

Participants

Twenty-five PD patients from the Movement Disorders outpatient clinic at the Royal Melbourne Hospital provided informed consent to participate in the study, which was approved by the Human Research Ethics Committee of Melbourne Health. Participants had no dementia (Montreal cognitive assessment, MOCA<24) or co-morbidities that cause significant chronic pain other than osteoarthritis and depression as these conditions and comorbidities could potentially impact pain processing.

Procedures

The study was

Psychophysical data

Clinical data of the 25 PD patients are summarized in (Table 1), 12 suffered dyskinesia. Dyskinetic patients had significantly increased duration of disease (p = .003), more severe disease (p = .019), and were on higher levodopa equivalent doses (p < .001). The severity of dyskinesia was relatively mild [average MAIMS 4.6 ± 0.9, (1−11)]. Both groups were matched for age, gender, side of more severe parkinsonism, cognition and mood. The prevalence of persistent pain was not increased in the

Discussion

In this study we examined the relationship between pain and dyskinesia with the utility of psychophysical and fMRI techniques. We found that dyskinetic PD patients had reduced JNP thresholds, increased pain ratings to fixed pressure stimuli, and a shift of the stimulus-response function to the left when compared to non-dyskinetic PD patients on psychophysical testing to pressure stimuli. This was accompanied by increased pain related BOLD activation in brain areas traditionally associated with

Contributors

Study concept and design-SS, MF, AE

Data Acquisition and analysis-SS, MF

Drafting and critical analysis of manuscript-SS, NV, MF, AE

Funding

None.

Declaration of Competing Interest

NV has received educational support from Abbvie, Stada, Ipsen and Merc, Speakers Honorarium from Abbvie & Stada and advisory board honorarium from Abbvie.

AHE reports reimbursement of travel expenses to scientific meetings or honoraria for lecturing or consultation from UCB, Teva, Stada, Allergan, Merz, Abbott and Abbvie, advisory board honoraria from Abbvie, Allergan, Stada and UCB; and holds shares in CSL and Global Kinetics Corporation.

Acknowledgements

None.

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