Abstract Details

Title Decoy Peptide Disruption of Neuronal Signaling Suggests a Novel Pharmacologic Target for Pain States

Topic Pain

Presentation(s) S52 - From Bench to Bedside with Novel Treatments for Pain (4:06 PM-4:18 PM)

Poster/Presentation
Number 004

Objective To study and evaluate potential signaling mechanisms and cascades of the neuro-inflammatory system, in an effort to identify future targets for benefit within clinical practice of pain management.

Background Pro-inflammatory signaling continues to be investigated as a integral component of neuropathic pain. Accumulating evidence indicates that both Toll-like receptor (TLR) and Receptor for Advanced Glycation End-products (RAGE) signal via similar adaptor protein cascades. Following ligand activation of the RAGE and TLR receptors within the nervous system, both intracellular signaling and recruitment of the signaling adaptor proteins MyD88 and TIRAP to the intracytoplasmic domain is initiated and contributes to neuronal activity. Further dissection of this mechanism and its complex signaling network of neuro-inflammation as it relates to the process of pain, may prove key to the advancement of clinical medicine and the essential focus of improving patient care.

Design/Methods In this study we investigated the degree to which acutely dissociated nociceptive neurons activity as measured by ratiometric calcium imaging and sharp electrode intracellular recording can be modified in the presence of decoy peptides designed to target MyD88 or TIRAP. Additional in vivo studies were performed to determine the ability of these peptides to alter behavioral responses to tactile stimulus in a model of rodent opioid-induced hyperalgesia.

Results TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Similar findings were demonstrated through the use of the TAT-TR6 peptide in primary cell culture. Acute systemic administration of the TAT-4BB and TAT-TR6 peptides reversed tactile allodynia in a dose-dependent manner.

Conclusions These data suggest that targeting the adaptor protein components of TLR4 and RAGE signaling cascades can potentially provide novel pharmacological targets to reduce or reverse neuropathic pain behavior in the clinical forum.

Authors/Disclosures
Yohance M. Allette, MD, PhD (Penn State Health Hershey Medical CEnter) PRESENTER	Dr. Allette has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Allette has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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