Parkinson's disease and pain: Modulation of nociceptive circuitry in a rat model of nigrostriatal lesion

Domenici, R.A.; Campos, Aria Carolina P.; Maciel, S.T.; Berzuino, Miriã Benatti; Hernandes, Marina S.; Fonoff, Erich Talamoni; Pagano, Rosana L.

doi:10.1016/j.expneurol.2019.02.007

Cited by 45 publications

(44 citation statements)

References 93 publications

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“…There is already strong evidence supporting a good level of predictive validity of the 6-OHDA rat for modelling pain in PD. For example, the reduced mechanical thresholds have been shown to return to baseline upon administration of L-DOPA, 68 consistent with the fluctuations in SPPD and reversal of pain in patients upon L-DOPA administration. 14,21,22,33 Furthermore, non-pharmacological interventions that are efficacious in the clinic such as the afore-mentioned DBS of the STN 69 are also back translated into this model.…”

Section: -Ohdamentioning

confidence: 53%

“…35 Moreover, apomorphine, which was ineffective in patients, 24 has been shown to reverse hypersensitivity in this model. 68 It is clear therefore that predictive validity is strong, but that extra caution should be applied to avoid identifying false positives. Given its reasonable face and predictive validity, the 6-OHDA rat model is likely to prove useful for investigations aimed at gaining mechanistic insight into the hypersensitivity seen.…”

Section: -Ohdamentioning

confidence: 99%

“…This is consistent with the analgesic benefits provided by oxycodone/naloxone in PD patients with severe pain 25,27 and is further supported by the findings of bilateral reductions in enkephalins and μ-opioid receptors and increased excitability of lamina V wide dynamic range neurons in the spinal cord of unilaterally 6-OHDA lesioned rats which expressed mechanical and heat hypersensitivity. 68,76 Serotonergic involvement in the nociceptive hypersensitivity is also implicated. For example, 6-OHDA lesioned rats with nociceptive hypersensitivity show reduced numbers of 5-HT neurons in the rostral ventromedial medulla (RVM) and in the dorsal horn of the spinal cord, 77 suggestive of reduced 5-HT transmission in these pain related regions.…”

Section: -Ohdamentioning

confidence: 99%

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Potential of animal models for advancing the understanding and treatment of pain in Parkinson’s disease

Buhidma

Rukavina

Chaudhuri

et al. 2020

npj Parkinsons Dis.

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Pain is a commonly occurring non-motor symptom of Parkinson's disease (PD). Treatment of pain in PD remains less than optimal and a better understanding of the underlying mechanisms would facilitate discovery of improved analgesics. Animal models of PD have already proven helpful for furthering the understanding and treatment of motor symptoms of PD, but could these models offer insight into pain in PD? This review addresses the current position regarding pain in preclinical models of PD, covering the face and predictive validity of existing models and their use so far in advancing understanding of the mechanisms contributing to pain in PD. While pain itself is not usually measured in animals, nociception in the form of thermal, mechanical or chemical nociceptive thresholds offers a useful readout, given reduced nociceptive thresholds are commonly seen in PD patients. Animal models of PD including the reserpine-treated rat and neurodegenerative models such as the MPTP-treated mouse and 6hydroxydopamine (6-OHDA)-treated rat each exhibit reduced nociceptive thresholds, supporting face validity of these models. Furthermore, some interventions known clinically to relieve pain in PD, such as dopaminergic therapies and deep brain stimulation of the subthalamic nucleus, restore nociceptive thresholds in one or more models, supporting their predictive validity. Mechanistic insight gained already includes involvement of central and spinal dopamine and opioid systems. Moving forward, these preclinical models should advance understanding of the cellular and molecular mechanisms underlying pain in PD and provide test beds for examining the efficacy of novel analgesics to better treat this debilitating non-motor symptom.

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Section: -Ohdamentioning

confidence: 53%

Section: -Ohdamentioning

confidence: 99%

Section: -Ohdamentioning

confidence: 99%

See 1 more Smart Citation

Potential of animal models for advancing the understanding and treatment of pain in Parkinson’s disease

Buhidma

Rukavina

Chaudhuri

et al. 2020

npj Parkinsons Dis.

View full text Add to dashboard Cite

show abstract

“…At the behavioral level, regardless inconsistencies found through the scientific publications, p a r k i n s o n i a n a n i m a l s t e n d t o m i m i c t h e h u m a n symptomatology showing motor but also non-motor impairments (Titova et al, 2017). An array of studies report that rodents lesioned with 6-OHDA or MPTP show anxious and depressive behavior, pain, cognitive, and sleep disturbances (Monaca et al, 2004;Pérez et al, 2009;Berghauzen-Maciejewska et al, 2014;Vo et al, 2014;Kamińska et al, 2017;Charles et al, 2018;Campos et al, 2019;Domenici et al, 2019), more notably in bilateral models of the disease (Ferro et al, 2005;Tadaiesky et al, 2008;Santiago et al, 2010;Bonito-Oliva et al, 2014;Vieira et al, 2019). Although the participation of other nuclei cannot be ruled out, the role of the LC in the mentioned functions is widely accepted.…”

Section: Preclinical Evidencementioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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“…Apomorphine-induced rotational behavior was evaluated in order to validate the PD model, since the number of asymmetric rotations correlates with the degree of nigral degeneration, as previously demonstrated (Domenici et al 2019). Rotational asymmetric behavior was evaluated using an automatic rotometer system (Rota-Count 8, Columbus Instruments, OH, USA) 7 days after striatal saline or 6-OHDA injections.…”

Section: Apomorphine-induced Rotational Behaviormentioning

confidence: 99%

Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson’s Disease Rat Model

et al. 2020

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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

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Parkinson's disease and pain: Modulation of nociceptive circuitry in a rat model of nigrostriatal lesion

Cited by 45 publications

References 93 publications

Potential of animal models for advancing the understanding and treatment of pain in Parkinson’s disease

Potential of animal models for advancing the understanding and treatment of pain in Parkinson’s disease

The Noradrenergic System in Parkinson’s Disease

Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson’s Disease Rat Model

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