Targeting Endosomal Receptors for Treatment of Chronic Pain

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: NIGEL W BUNNETT
Organization: NEW YORK UNIVERSITY
Fiscal Year: 2024
Award: $795,324
Funding agency: National Institute of Dental and Craniofacial Research

PROJECT SUMMARY/ABSTRACT
Pharmacologic therapy for common forms of chronic pain is ineffective and plagued with side effects. Our long-
term goal is to reveal mechanisms of pain/nociceptive signaling and define drug targets. G protein-coupled
receptors (GPCRs) control most patho-physiological processes, including pain, and are the target of 34% of
therapeutic drugs. GPCRs are considered to function solely at the plasma membrane, where they interact with
extracellular ligands and couple to intracellular G proteins. However, agonists released from injured and
diseased tissues evoke redistribution of GPCRs to endosomes in neurons. These endosomal GPCRs
(eGPCRs) generate sustained signals in subcellular compartments that control the ion channel activity that
underlies chronic pain. The central hypothesis is that activation of pronociceptive eGPCRs produces
nociceptive signaling and most forms of chronic pain; antagonists of eGPCRs block nociceptive signaling and
are anti-nociceptive. The rationale for this proposal is that discovery of eGPCR pain mechanisms will facilitate
development of drugs that selectively antagonize eGPCRs in neurons and provide superior pain relief with
fewer side effects. The overall objectives are to discover mechanisms underlying chronic pain and validate a
therapeutic target. The central hypothesis will be tested by pursuing three specific aims: 1) Discover the
mechanisms of eGPCR signaling in subcellular compartments of neurons; biophysical and imaging
approaches will be used; nanoparticles (NPs) will be designed with components that target neurons, promote
endocytosis and release eGPCR ligands in the acidic endosome; 2) Discover the mechanisms by which
eGPCRs regulate ion channels that control neuron activity; ion channel activity and excitability of neurons will
be studied with electrophysiology. NP-encapsulated drug probes will define the role of eGPCRs in neuronal
excitation; 3) Validate eGPCRs as a therapeutic target for chronic inflammatory, neuropathic and cancer pain;
NP-encapsulated eGPCR ligands will be compared to conventional therapy in three pain models. The
proposed pain mechanism is a novel explanation that resolves the enigma of widespread clinical trial failures of
GPCR-targeted drugs. Innovation in the proposal extends to the NP approach to probe the mechanism and
validate the target. The proposal is clinically significant because it validates an eGPCR-target that offers
superior pain relief with fewer side-effects and is applicable to most patients with intractable chronic pain.

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