Summary
A bioRxiv preprint reports that brain-originating dopaminergic neurodegeneration can produce persistent NaV1.7-dependent hyperexcitability in peripheral sensory neurons in a preclinical Parkinson’s model. Blocking NaV1.7 or disrupting its CRMP2 regulation reduced pain-like behaviours, while human Parkinson’s DRG profiling found related excitability-gene changes.
A bioRxiv preprint reports that neurodegeneration originating in the brain can cause persistent changes in peripheral pain-sensing neurons in a Parkinson’s disease model. The researchers link the changes to NaV1.7, a voltage-gated sodium channel that helps control how readily sensory neurons generate electrical signals.
In the preclinical experiments, selectively blocking NaV1.7 or disrupting its regulation by the protein CRMP2 reduced pain-like behaviours. The study also found selective changes in genes associated with sensory-neuron excitability in dorsal root ganglion tissue from people with Parkinson’s disease. The findings point to a peripheral pain mechanism that is distinct from the motor features of Parkinson’s disease, but they remain preclinical results from a bioRxiv preprint.
How Parkinsonian neurodegeneration altered pain signalling
Pain is a common and disabling nonmotor symptom of Parkinson’s disease, but the biological processes producing it are not fully defined. The researchers used a brain-restricted 6-hydroxydopamine model to examine whether nigrostriatal neurodegeneration could affect sensory neurons outside the central nervous system.
Small-diameter neurons in the dorsal root ganglia showed increased sodium current density and altered voltage-dependent inactivation. Dorsal root ganglia contain the cell bodies of many peripheral sensory neurons. Sodium-channel inactivation normally helps limit repeated or prolonged firing; changes in this process can make neurons more excitable.
The excess sodium current was eliminated by selective NaV1.7 blockade, placing the channel at the centre of the observed electrical change. In the same model, the researchers found mechanical and thermal hypersensitivity, behavioural measures used to represent pain-like responses in animals.
Safinamide provided a second connection to the pathway. The drug, which has been reported to improve pain in some people with Parkinson’s disease, directly inhibited a NaV1.7-dependent component of sensory-neuron sodium current in the experiments and reversed established pain-like behaviours. This gives the researchers a proposed mechanism for a pain-related effect associated with the drug, rather than treating the finding as evidence of a new clinical indication.
CRMP2 regulation separates pain from the motor phenotype
The study focused on how CRMP2 regulates NaV1.7. Pharmacologically disrupting this regulatory process normalised the heightened excitability of dorsal-root-ganglion neurons and reversed both mechanical and thermal hypersensitivity.
A genetic experiment strengthened the connection. Disrupting the NaV1.7 regulatory sequence targeted by CRMP2 prevented the development of 6-hydroxydopamine-induced pain-like behaviours for up to 30 weeks. The Parkinsonian motor phenotype was preserved during this period, indicating in the model that the intervention affected the pain-related pathway without preventing the motor consequences of the neurodegeneration.
The authors also analysed gene activity in human Parkinson’s disease dorsal root ganglia. The tissue showed limited broad transcriptional remodelling, alongside selective changes in genes associated with sensory-neuron excitability. This human molecular result is consistent with the proposed peripheral mechanism, while the behavioural and electrophysiological evidence came from the preclinical model.
The findings identify CRMP2-dependent control of NaV1.7 as a possible target for Parkinsonian pain. NaV1.7-directed treatments would need to be evaluated for efficacy and safety in people with Parkinson’s disease before the pathway could be considered a clinical treatment strategy. The study is a bioRxiv preprint and has not yet undergone journal peer review. Its authors report that Rajesh J. Khanna is the founder of Regulonix LLC, a company developing non-opioid drugs for chronic pain.