Study Reveals Mechanisms Underlying Pain Processing in Parkinson’s Disease

A novel pain-sensing brain network links pain in Parkinson’s disease to a specific region of the brain, called the subthalamic nucleus, an animal study has found.

The findings illustrate why this specific brain region is a potential target for pain relief in Parkinson’s, as well as in Huntington’s disease, and other neurodegenerative disorders.

The study, “Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing,” was published in the journal eLIFE.

Pain is one of Parkinson’s non-motor symptoms and may manifest as burning, stabbing, aching, itching or tingling sensations. Scientists believe that these symptoms, which are not directly related to the pain caused by the disorder’s motor symptoms, result from dysfunction of the central nervous system.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), a brain area involved in motor function that is hyperactive in Parkinson’s patients, is an effective technique to ease motor dysfunction. This surgical treatment also has been shown to weaken pain intensity, but the mechanism underlying this benefit remains unclear.

Early studies have indicated that the STN could be part of a network involved in pain perception, but little is known about the type of sensory stimulus activating this brain area.

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“We set out to determine whether the [STN] is involved in translating a harmful stimulus such as injury into pain, and whether this information transmission is altered in [Parkinson’s],” Arnaud Pautrat, the study’s lead author, said in a press release.

The research team from France and the U.K. conducted electrophysiology (electrical activity) experiments in rats subjected to a shock to the hind paw. This showed that neurons in the STN could be separated into three groups, depending on whether their electrical activity increased, decreased or was unchanged upon being shocked. Most of the responsive cells changed their activity specifically after pain stimulation and not other types of stimuli.

Then, the team explored if damage to the STN changed these responses. Results showed that rats with lesions in this brain area took much longer to manifest discomfort in comparison to controls.

Subsequent experiments in a rat model of Parkinson’s revealed that neurons in the STN had higher firing rate (greater activity) and exhibited bigger and longer responses to pain than healthy animals. According to researchers, these findings suggest that Parkinson’s-associated pain is caused by impaired pain processing in this brain area.

To understand where pain signals in the STN could come from, the team focused on the superior colliculus and the parabrachial nucleus, two brain areas that relay damage signal originating from the spinal cord.

Blocking the activity or damaging these regions changed the number of STN cells responding to pain, revealing the key role of both regions. Also, researchers found that the parabrachial nucleus and the STN are directly connected.

“We have found evidence that the [STN] is functionally linked to a pain-processing network and that these responses are affected in Parkinsonism,” said Veronique Coizet, PhD, the study’s senior author. Of note, Parkinsonism is a general term for neurological disorders that cause movement problems similar to those of Parkinson’s patients.

Overall, the team believes this network is possibly implicated in the pain relief achieved with DBS in Parkinson’s patients. Coizet noted that more work is necessary to fully characterize the effects of DBS on the STN in animal models.

“The STN-DBS technique can thus be considered in the future as a new target for the treatment of pain in pharmaco-resistant patients suffering from previously described neurodegenerative disease, but also, for example, in chronic pain disease or pharmaco-resistant patients with certain form of migraine,” researchers wrote.

“Further experiments are now needed to fully characterize the effects deep brain stimulation on this brain region in our experimental models, with a view to finding ways to optimize it as a treatment for pain caused by Parkinson’s and other neurological diseases,” Coizet added.