A generation ago, scientists discovered that the nervous system produces its own morphine-like, pain-relieving substances—the endorphins—which latch onto receptors on the surface of selected nerve cells to initiate their analgesic action. These “opioid” receptors come in several subtypes given Greek letter names (mu, kappa, delta) and respond to a range of opioid drugs such as morphine and codeine. The problem is that cells with opioid receptors are abundant in the nervous system where they serve multiple functions, and prescription opioids are not selective. The result is that most pain patients taking such drugs experience unpleasant side effects, including nausea, constipation, lower respiration rate, and so on, not to mention the potential for addiction. If chemists could refine their drug designs to target selected subtypes of opioid receptors the hope is that these unwanted side effects would be eliminated.
That hope is closer to reality now as a result of the research of two teams of investigators published in the online March 21 edition of Nature. A team led by Brian Bobilka and Sébastien Granier at Stanford University School of Medicine has detailed the structure of the mu opioid receptor, which responds to morphine and other analgesics, and a team at the Scripps Research Institute in La Jolla, California headed by Raymond Stevens has done the same for the kappa opioid receptor. The receptor structures are complex molecules that criss-cross the nerve cell membrane and each contains a large pocket that could bind a candidate drug at different spots. The idea would be to design molecules that would bind tightly and selectively to particular subtypes and in such a way as to activate just the right pathways to relieve pain and not produce unwanted side effects. No one is promising that new magic bullet pain drugs will be produced overnight. To complicate matters, researchers are discovering that the receptor structure is not static, but can alter its form, which could in turn alter what compounds could fit into it. At least investigators have a starting point for rational drug design, ushering in what some are already calling a new era in opioid pharmacology.
Joan Wilentz, The TMJ Association
Source: Pain Research Forum, http://www.painresearchforum.org
Update: The same teams of investigators have determined the structure of two moreopioid receptors. Stanford scientists solved the structure of the delta receptor and the Scripps team the nociceptin/orphin FQ receptor.