Study rationale

Chronic pain is a common and debilitating symptom in both Parkinson’s disease (PD) and dystonia, which significantly reduces patients’ quality of life. The NaV1.7 sodium channel, encoded by the SCN9A gene, plays a critical role in pain transmission and is upregulated in PD patients, potentially contributing to pain severity. The proposal suggests that targeting NaV1.7 via Compound 194—a regulator that reduces NaV1.7 activity in sensory neurons—could alleviate pain in these conditions.

Hypothesis

The study hypothesizes that:

1. NaV1.7 and CRMP2 (a related protein) are upregulated in the dorsal root ganglion (DRG) neurons of both MPTP-treated mice (a PD model) and human PD patients.
2. Treatment with Compound 194 will reduce pain-like behaviors and NaV1.7 activity in MPTP-treated mice, as well as reduce hyperexcitability in the parabrachial nucleus (PBN), which is involved in pain transmission.

study design

The study comprises three specific aims:

1. Evaluate NaV1.7 expression in DRG neurons from PD mouse models and human PD patient samples using quantitative FISH analysis.
2. Assess the analgesic efficacy of Compound 194 by testing its impact on pain behaviors and NaV1.7 activity in MPTP-treated mice.
3. Investigate PBN hyperexcitability using fiber photometry to track PBN neuron activity over time in both MPTP-treated and dystonia model mice.

impact on dystonia treatment

If successful, this study could provide the foundation for novel treatments targeting NaV1.7 to alleviate chronic pain in dystonia patients, addressing an unmet need for effective pain management in both PD and dystonia. By reducing pain, the treatment could improve the quality of life and physical function for individuals affected by these disorders.

next steps for development

Future steps involve:

1. Applying for further funding through K99/R00 and R21 grants to support additional research on pain mechanisms in neuromuscular disorders.
2. Extending the research to examine pain mechanisms across various neurological conditions, including different dystonia models, in collaboration with the Norman Fixel Institute for Neurological Diseases.

other relevant information

The project is intended to provide preliminary data critical for securing further funding, ultimately supporting the lead investigator’s goal of establishing an independent research lab focused on pain in neuromuscular disorders. This proposal also aims to foster interdisciplinary collaboration for broader impacts in pain research.

study team

The study team consists of Dr. Tyler S. Nelson as the principal investigator, responsible for overseeing all experimental aspects, data analysis, and publication efforts, and Dr. Rajesh Khanna as the mentor, who will provide scientific guidance and ensure research rigor. Together, they aim to generate critical preliminary data that will support further grant applications and establish a foundation for future research on pain in PD, dystonia, and related neurological disorders.