Nociceptive Response to l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats

Abstract

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.

Pain in Parkinson's disease: new concepts in pathogenesis and treatment

“…Furthermore, mechanical thresholds can be measured via von Frey filaments and the Randall-Selitto test. These tests have been widely applied to both unilateral and bilateral 6-OHDA lesion models [22][23][24][25][26][27][28][29][30][31][32], MPTP [33] and Pitx3 416insG (mutation in the transcription factor Pitx3 selective to dopamine neurons) rodent models [34], with results consistently revealing hyperalgesia in the affected paw. The use of Parkinson's disease models with a pain component are crucial not only for a better understanding of the cellular and molecular mechanisms involved in disease associated nociception, but also as a platform for analgesic testing.…”

Motor Cortex Stimulation Reversed Hypernociception, Increased Serotonin in Raphe Neurons, and Caused Inhibition of Spinal Astrocytes in a Parkinson’s Disease Rat Model

“…Persistent pain is one of the most common nonmotor symptoms of PD and contributes to its complexity [ 7 , 8 , 65 ]. The gold standard treatment for PD is dopamine replacement, which improves motor and nonmotor symptoms, including pain [ 15 , 17 , 19 ]. However, long-term dopamine therapy induces severe side effects that diminish the quality of life in individuals with PD [ 18 , 66 ].…”

“…Dopamine replacement in PD patients and experimental models has shown positive results in decreasing pain sensitivity [ 15 , 16 , 17 ]. However, long-term dopaminergic therapy can lead to undesirable effects, such as motor fluctuations during off-periods of the drug, dyskinesia, and pain hypersensitivity, which are associated with disease progression and drug exposure; this, in turn, exponentially worsens quality of life [ 18 , 19 , 20 ]. Beside dopamine, serotonin deficit also plays a major role in PD pathophysiology and is related to nonmotor symptoms such as pain and depression [ 21 , 22 , 23 , 24 , 25 ].…”

Interplay between endocannabinoids and dopamine in the basal ganglia: implications for pain in Parkinson’s disease

“…Intriguingly, toxin-induced rodent models of PD (i.e., MPTP and 6-OHDA) have provided a valuable contribution in understanding the role of DA in pain process. Similar to humans, DA-depleted animals show an increased nociception and decreased nociceptive threshold [ 10 , 100 – 104 ] suggesting that the loss of DA in the basal ganglia is involved in the reduction of pain threshold [ 105 ]. Of note, the elevation of striatal DA following electrical stimulation of the SN or the direct striatal administration of apomorphine, a D1/D2-R agonist, induces pain inhibition [ 106 ].…”