“A better understanding of these mechanisms will enable us to design drugs that avoid body resistance to these drugs and produce longer therapeutic responses, including longer-acting opioid analgesics”, lead author Dr. Graciela Pineyro said.
Humans have known about the usefulness of opioids, which are often harvested from poppy plants, for centuries, but we have very little insight into how they lose their effectiveness in the hours, days and weeks following the first dose. “Our study revealed cellular and molecular mechanisms within our bodies that enable us to develop resistance to this medication, or what scientists call drug tolerance,” she added.
The research team looked at how drug molecules would interact with molecules called “receptors” that exist in every cell in our body. Receptors, as the name would suggest, receive “signals” from the chemicals that they come into contact with, and the signals then cause the various cells to react in different ways. They sit on the cell wall, and wait for corresponding chemicals known as receptor ligands to interact with them. Ligands can be produced by our bodies or introduced, for example, as medication.
“Until now, scientists have believed that ligands acted as ‘on-off’ switches for these receptors, all of them producing the same kind of effect with variations in the magnitude of the response they elicit,” Pineyro explained. “We now know that drugs that activate the same receptor do not always produce the same kind of effects in the body, as receptors do not always recognize drugs in the same way. Receptors will configure different drugs into specific signals that each will have different effects on the body.”
Once activated by a drug, receptors move from the surface of the cell to its interior, and once they have completed this ‘journey’, they can either be destroyed or return to the surface and used again through a process known as “receptor recycling.” By comparing two types of opioids – DPDPE and SNC-80 – the researchers found that the ligands (chemicals that enable interaction with the cell) that encouraged recycling produced less analgesic tolerance than those that didn’t. “We propose that the development of opioid ligands that favour recycling could be a way of producing longer-acting opioid analgesics,” Pineyro said.
Pineyro is attempting to tease the “painkilling” function of opioids from the part that triggers mechanisms that enable tolerance build up. “My laboratory and my work are mostly structured around rational drug design, and trying to define how drugs produce their desired and non-desired effects, so as to avoid the second, Pineyro said. “If we can understand the chemical mechanisms by which drugs produce therapeutic and undesired side effects, we will be able to design better drugs.”
The study “Differential association of receptor-Gβγ complexes with β-arrestin2 determines recycling bias and potential for tolerance of delta opioid receptor (DOR) agonists” was published in The Journal of Neuroscience on April 3, 2012. The research was funded by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. Dr. Graciela Pineyro, MD, PhD is affiliated with the Departments of Psychiatry and Pharmacology at the University of Montreal and the Sainte-Justine University Hospital Center (UHC)’ Research Center. The University of Montreal and the Sainte-Justine UHC’s Research Centre are officially known as Université de Montréal and Centre de recherche du Centre hospitalier universitaire Sainte-Justine, respectively.
- Profile of Graciela Pineyro
- Faculté de médecine de l’Université de Montréal
- Centre de recherche du CHU Sainte-Justine
- Natural Sciences and Engineering Research Council of Canada
- Canadian Institutes of Health Research
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