Poster: Membrane Transport

Abs # 1223: Electrophysiological analysis of anandamide/capsaicin hybrid analogs in Xenopus oocytes expressing VR1: discovering therapeutic agents in pain prevention

Presenter:	Mercier, Richard W, rmercier@canr.cag.uconn.edu
Authors	Mercier, Richard W (A)   Makriyannis, Alexandros  (A)   Li, Chen  (A)   Berkowitz, Gerald A (A)
Affiliations:	(A): University of Connecticut

A pain sensation is experienced when sensory neurons are activated by noxious stimuli. These neurons or nociceptors are characterized in part by their sensitivity to capsaicin (a vanilloid compound), the active ingredient in chilli peppers. However, it has long been known that repeated exposure to capsaicin leads to pain attenuation. This phenomenon has been exploited in pain mitigating botanical preparations for centuries. Electrophysiological analysis of the pain receptor (VR1), a nociceptor-associated non-selective ligand gated cation channel, provides a novel means to identify other compounds clinically useful in pain intervention. Binding of capsaicin and vanilloid-like compounds to VR1 initiates a complex and, to date, poorly understood cascade of events which may be described by three distinguishable phenomena, including 1) excitation 2) desensitization and 3) tachyphylaxis. Evidence suggests that neuronal desensitization or tachyphylaxis is caused by a loss of channel activity. Recently it was discovered that anandamide, the endogenous ligand for cannabinoid receptors, also activates VR1. In this report we describe a series of synthetic VR1 agonists which incorporate components of the anandamide and capsaicin molecules. Utilizing Xenopus oocytes as a heterologous expression system and two-electrode voltage clamp electrophysiology we observe these compounds to directly activate the channel at a level significantly greater than capsaicin. In addition, upon repeated exposure of the novel hybrids both desensitization and tachyphylaxis is detected. This work may lead to to the identification of new compounds which have clinical use as analgesics.