Regulation of N-type calcium channel activity by Opioid receptor-like receptor - a novel mechanism to eliminate morphine tolerance

Prolonged morphine treatment is known to cause an up-regulation of ORL1 receptors in the spinal cord (12, 13), which in turn is believed to contribute to the development of morphine tolerance by altering ?-opioid receptor mediate modulation of N-type calcium channels. Indeed, ORL1 antagonists can reverse the development of tolerance, and ORL1 knockout can mediate resistance to tolerance with no changes on the acute analgesic effects of morphine (14, 15). Our lab has shown that ORL1 receptors and Cav2.2 channels form a physical signaling complex that results in tonic G?? inhibition of the channel activity and that this modulation can happen simply by changes in ORL1 receptor density, in an agonist-independent way (16, 17). I hypothesize that the channels that are in a complex with ORL1 receptors, can no longer be inhibited by classical opioids and, thereby contributing to morphine tolerance. Under the Mitacs fellowship, I propose to develop strategies to selectively disrupt the channel-receptor interaction and examine how this will affect the transmission of pain and the tolerance to opioids. I expect to first identify the molecular details of the channel/ receptor interaction site and then, design cell-permeable Tat-peptides to disrupt the interaction in vitro and in vivo.

Ivana Assis Souza
Superviseur universitaire: 
Dr. Gerald Werner Zamponi
Project Year: