In a new study, researchers discovered that pharmaceutical opioids produce their effects by binding to receptors inside neurons; this is contrary to previous theories that these drugs acted only on the same surface receptors as the body’s natural endogenous opioids.
This difference between how medically used and naturally made opioids interact with nerve cells may help guide the development of pain relievers that do not lead to addiction or other negative effects produced by opioid medications.
“This ground-breaking study has uncovered important distinctions between the opioids that our brain makes naturally and therapeutic opioids that can be misused,” said Nora D. Volkow, M.D., director of the National Institute on Drug Abuse (NIDA).
“This information can be mined to better understand the potential adverse actions of medically prescribed opioids and how to manipulate the endogenous system to achieve optimal therapeutic results without the unhealthy side effects of tolerance, dependence, or addiction.”
Both naturally occurring opioids and medically used opioids bind to the mu-opioid receptor, a member of a widespread family of proteins known as G protein-coupled receptors (GPCRs).
Recent advances in understanding the three-dimensional structure of GPCRs have allowed scientists to develop a new type of antibody biosensor, called a nanobody, that produces a fluorescent signal when a GPCR is activated. This allows scientists to track chemicals as they move through cells and respond to stimuli.
Using this nanobody, the scientists first showed that when a naturally occurring opioid binds to and activates the mu-receptor on the surface of a neuron, receptor molecules enter the cell inside what is known as an endosome. There, the mu-receptor remains activated over a period of several minutes, which itself was a new discovery, since it was previously thought that the opioid receptor is only activated on the surface of nerve cells.
Proteins that interact with receptors on the cell surface control a variety of biological processes and provide targets for therapeutic intervention.
Regarding pharmaceutical opioids, however, the scientists made two additional discoveries. First, they found that there are significant differences among various opioid drugs in how strongly they induce receptor activation in endosomes.
Second, the opioid drugs uniquely induce rapid nanobody signaling, within tens of seconds, in an internal cellular structure known as the Golgi apparatus in the main body of the neuron. Further investigation showed that therapeutic opioids also uniquely activate mu-opioid receptors in related structures, known as Golgi outposts, in the long, branched structures of neurons.
“We were surprised to see that drugs such as morphine activate opioid receptors in a location at which naturally occurring opioids do not,” said Dr. Mark von Zastrow, senior author of the study.
Based on these findings, the scientists hypothesize that pharmaceutical opioids distort the normal time and spatial sequence of mu-opioid receptor activation and signaling.
This distortion may help explain the undesired side effects of opioid drugs and suggest new avenues for developing agents that do not lead to addiction or the other adverse effects often associated with these drugs.
“This new biosensor opens our eyes to a previously unknown level of diversity and specificity in the cellular actions of opioids,” said Dr. Miriam Stoeber, the study’s first author.
Source: National Institute on Drug Abuse
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