Nociceptive Response to l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats
- 95 Downloads
Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson’s disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, l-DOPA (l-3,4-dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating l-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease to a hind paw-induced persistent inflammation. Further, the effect of l-DOPA on nociception behavior at different times of treatment was investigated. Pain threshold was determined using von Frey and Hot Plate/Tail Flick tests. Dyskinesia was measured by abnormal involuntary movements (AIMs) induced by l-DOPA administration. This data is consistent to show that 6-OHDA-lesioned rats had reduced nociceptive thresholds compared to non-lesioned rats. Additionally, when these rats were exposed to a persistent inflammatory challenge, we observed increased hypernociceptive responses, namely hyperalgesia. l-DOPA treatment alleviated pain responses on days 1 and 7 of treatment, but not on day 15. During that period, we observed an inverse relationship between LID and nociception threshold in these rats, with a high LID rate corresponding to a reduced nociception threshold. Interestingly, pain responses resulting from CFA-induced inflammation were significantly enhanced during established dyskinesia. These data suggest a pro-algesic effect of l-DOPA-induced dyskinesia, which is confirmed by the correlation founded here between AIMs and nociceptive indexes. In conclusion, our results are consistent with the notion that central dopaminergic mechanism is directly involved in nociceptive responses in Parkinsonism condition.
KeywordsHyperalgesia l-DOPA-induced dyskinesia 6-OHDA toxin Parkinson’s disease
We would like to thank Célia Aparecida da Silva for the technical support. The equipment and drugs used in this work were acquired from FAPESP, CNPq, CAPES, Brazil. The experiments presented in this manuscript comply with the current Brazilian laws. This manuscript was revised by Elsevier Language Editing Services (Elsevier Webshop).
Compliance with Ethical Standards
The experiments were performed in compliance with the recommendations of SBNeC (Brazilian Society of Neuroscience and Behavior), which are based on the US National Institutes of Health Guide for Care and Use of Laboratory Animals. The local Ethical Committee approved the protocol.
The authors declare that they have no competing interests.
- Chang JW, Wachtel SR, Young D, Kang UJ (1999) Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson's disease: studies on medial forebrain bundle and striatal lesions. Neuroscience 88(2):617–628Google Scholar
- Chen Y, Mao CJ, Li SJ, Wang F, Chen J, Zhang HJ, Li L, Guo SS, Yang YP, Liu CF (2015) Quantitative and fiber-selective evaluation of pain and sensory dysfunction in patients with Parkinson’s disease. Parkinsonism Relat 21:361–365. https://doi.org/10.1016/j.parkreldis.2015.01.008 CrossRefGoogle Scholar
- Cury RG, Galhardoni R, Teixeira MJ, Dos Santos Ghilardi MG, Silva V, Myczkowski ML, Marcolin MA, Barbosa ER, Fonoff ET, Ciampi de Andrade D (2016) Subthalamic deep brain stimulation modulates conscious perception of sensory function in Parkinson's disease. Pain 157:2758–2765. https://doi.org/10.1097/j.pain.0000000000000697 CrossRefPubMedGoogle Scholar
- Dieb W, Ouachikh O, Alves S, Boucher Y, Durif F, Hafidi A (2016) Nigrostriatal dopaminergic depletion increases static orofacial allodynia. J Headache Pain 17:11. https://doi.org/10.1186/s10194-016-0607-z. Epub2016Feb 17
- Evans AH, Lawrence AD, Potts J, Appel S, Lees AJ (2005) Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease. Neurology 65:1570–1574. https://doi.org/10.1212/01.wnl.0000184487.72289.f0. CrossRefPubMedGoogle Scholar
- Gomes MZ, Del Bel EA (2003) Effects of electrolytic and 6-hydroxydopamine lesions of rat nigrostriatal pathway on nitric oxide synthase and nicotinamide adenine dinucleotide phosphate diaphorase. Brain Res Bull 62:107–115. https://doi.org/10.1016/j.brainresbull.2003.08.010 CrossRefPubMedGoogle Scholar
- Gomes MZ, Raisman-Vozari R, Del Bel EA (2008) A nitric oxide synthase inhibitor decreases 6-hydroxydopamine effects on tyrosine hydroxylase and neuronal nitric oxide synthase in the rat nigrostriatal pathway. Brain Res 1203:160–169. https://doi.org/10.1016/j.brainres.2008.01.088 CrossRefPubMedGoogle Scholar
- Guigoni C, Li Q, Aubert I, Dovero S, Bioulac BH, Bloch B, Crossman AR, Gross CE, Bezard E (2005) Involvement of sensorimotor, limbic, and associative basal ganglia domains in l-3,4-dihydroxyphenylalanine-induced dyskinesia. J Neurosci 25:2102–2107. https://doi.org/10.1523/JNEUROSCI.5059-04.2005 CrossRefPubMedGoogle Scholar
- Iwaszkiewicz KS, Hua S (2014) Development of an effective topical liposomal formulation for localized analgesia and anti-inflammatory actions in the complete Freund’s adjuvant rodent model of acute inflammatory pain. Pain Physician 17:19–35Google Scholar
- Jarcho JM, Mayer EA, Jiang ZK, Feier NA, London ED (2012) Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction. Pain 153:744–754. https://doi.org/10.1016/j.pain.2012.01.002. Epub2012 Mar 3.
- Kirik D, Rosenblad C, Björklund A (1998) Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152(2):259–277Google Scholar
- Marques A, Chassin O, Morand D, Pereira B, Debilly B, Derost P, Ulla M, Lemaire JJ, Durif F (2013) Central pain modulation after subthalamic nucleus stimulation: a crossover randomized trial. Neurology 81:633–640. https://doi.org/10.1212/WNL.0b013e3182a08d00. Epub2013Jul 17
- Mylius V, Gerstner A, Peters M, Prokisch H, Leonhardt A, Hellwig D, Rosenow F (2009b) Low-frequency rTMS of the premotor cortex reduces complex movement patterns in a patient with pantothenate kinase-associated neurodegenerative disease (PKAN). NeurophysiolClin 39:27–30. https://doi.org/10.1016/j.neucli.2008.12.003 Google Scholar
- Padovan-Neto FE, Echeverry MB, Tumas V, Del-Bel EA (2009) Nitric oxide synthase inhibition attenuates l-DOPA-induced dyskinesias in a rodent model of Parkinson’s disease. Neuroscience 159:927–935. https://doi.org/10.1016/j.neuroscience.2009.01.034 CrossRefPubMedGoogle Scholar
- Saadé NE, AbouJaoude PG, Saadeh FA, Hamoui S, Safieh-Garabedian B, Kanaan SA, Atweh SF, Jabbur SJ (1997) Fos-like immunoreactivity induced by intraplantar injection of endotoxin and its reduction by morphine. Brain Res 769:57–65. https://doi.org/10.1016/S0006-8993(97)00662-8 CrossRefPubMedGoogle Scholar
- Schestatsky P, Kumru H, Valls-Solé J, Valldeoriola F, Marti MJ, Tolosa E, Chaves ML (2007) Neurophysiologic study of central pain in patients with Parkinson disease. Neurology 69:2162–2169. https://doi.org/10.1212/01.wnl.0000295669.12443.d3 CrossRefPubMedGoogle Scholar
- Wada A, Shizukuishi T, Kikuta J, Yamada H, Watanabe Y, Imamura Y, Shinozaki T, Dezawa K, Haradome H, Abe O (2017) Altered structural connectivity of pain-related brain network in burning mouth syndrome-investigation by graph analysis of probabilistic tractography. Neuroradiology 59:525–532. https://doi.org/10.1007/s00234-017-1830-2. Epub2017 Mar 30.
- Wang CT, Mao CJ, Zhang XQ, Zhang CY, Lv DJ, Yang YP, Xia KL, Liu JY, Wang F, Hu LF, Xu GY, Liu CF (2017) Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease. Mol Pain 13:174480691769152. https://doi.org/10.1177/1744806917691525 CrossRefGoogle Scholar
- Winkler C, Kirik D, Björklund A, Cenci MA (2002) L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of Parkinson’s disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 10:165–186. https://doi.org/10.1006/nbdi.2002.0499 CrossRefPubMedGoogle Scholar
- Wood JD (2008) Functional abdominal pain: the basic science. J Pediatr Gastroenterol Nutr 47:688–693. https://doi.org/10.1097/01.mpg.0000338961.40055.04 CrossRefPubMedGoogle Scholar