2023 MSC Poster Contest Presentation: Lipidated peptide targeted to Nav protein-protein interaction attenuates pain-like behaviors in rodent models of pain

The 2023 MSC Emerging Science Contest for Early-Career Investigators took place on December 13, 2023. Below is a written summary of one of the presentations from the contest. Read about other presentations from the event in our Early-Career Science Library.

Category: Pain

Winner: Rasheen Powell, postdoctoral researcher, Boston Children’s Hospital, US

Title: Lipidated peptide targeted to Nav protein-protein interaction attenuates pain-like behaviors in rodent models of pain.

Hypothesis, methodology, findings and conclusions.

Effective treatment of pain has been elusive due to complexities in the underlying mechanisms that drive nociception. Pharmacological blockade of ion channels that have been associated with pain (i.e., voltage-gated sodium channels Nav1.7 and Nav1.8) have had great success in pre-clinical pain models but have largely failed when translated to the clinic. The success of NSAIDs, gabapentinoids, and CGRP inhibitors for treating diverse pain states suggests that re-evaluating how we approach pharmacologically modulating nociceptors can lead to profound effects on pain sensation.

With this in mind, I have revisited the voltage-gated sodium channel responsible for nearly 80% of the upstroke of the action potential, Nav1.8. However, instead of blocking channel pore, to prevent sodium ion flux, I have decided to target the intercellular protein-protein interactions tethering Nav1.8 to cytoskeletal elements at the cell membrane. I hypothesize these interactions are crucial for Nav1.8 localization and stabilization in the membrane and disrupting these interactions would decrease Nav1.8 expression in neuronal membranes. Consequently, this is expected to decrease sodium flux across the membrane and attenuating neuronal firing, thus decreasing pain sensation.

First, I have developed a molecule capable of competing with Nav1.8 for its intracellular binding partners at the inner leaflet of the cell membrane. Using this molecule in cellular models of nociceptor hyperexcitability, it partially reversed various electrophysiological metrics associated with hyperexcitability. These metrics include sodium ion flux through voltage-gated ion channels, action potential height, action potential firing frequency, and rheobase (the minimal current a neuron requires to fire an action potential). When translated to animal models of pain, the same molecule was able to partially rescue pain-like behaviors associated with neuropathic and inflammatory insult. What is most surprising, however, is that a one-time local application of this molecule produced a pharmacological effect that lasted 7-9 days in some pain models. This would suggest that the mechanisms that underlie pain initiation and maintenance may be largely dependent on neuronal plasticity at the site of injury, and local modulation of these mechanisms can have prolonged and profound effects on pain sensation.

From a clinical perspective, these findings provide an innovative avenue for non-opioid pharmacological interventions for pain. Additionally, this molecule may serve as a prototype for a class of local, long-lasting analgesics that would function in a manner that addresses the molecular underpinnings of pain sensation, and not tangential contributors. Altogether, my research aims to deepen our understanding of pain mechanisms, and as a result, I have developed a molecule that is capable of rescuing pain-like behaviors in animal models that are associated with inflammatory and neuropathic pain.

Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.

As it stands, current advances in technology have produced more potent analgesics, however, their mechanisms of action are largely derivative of older drug classes. Efforts to develop new analgesics have produced a startingly low number of drugs that have successfully targeted new targets to achieve clinical pain relief. Even fewer therapeutics have been developed to effectively treat the primary or secondary drivers of migraine.

My research has begun to demystify the underlying molecular contributors to pain, broadening the field and paving the way for new analgesic interventions. If we can fully understand how peripheral nociceptors transition from a state of quiescence to hyperexcitability, we can identify the molecular interactions that are responsible for driving pain phenotypes. The success of CGRP inhibitors for treating migraine is a testament to this line of inquiry. By extending the scope of my research to include receptors necessary for nociceptor sensitization, I could envision a similar molecule that interacts with Cav2.1, Nav1.1, or any other membrane-bound receptor/ion channel known to progress the pathophysiology pf migraine.