Opioids work through the mu opiate receptors throughout the body and brain, dampening pain signals being sent through the peripheral nervous system and spinal cord. It also acts on the ventral tegmental area, causing the release of dopamine in the nucleus accumbens, creating a sensation of euphoria. It is this euphoric effect that seems to be most related to addiction potential. Opiates mimic our endogenous endorphins and have been used for millennia for pain treatment. Opioids are synthetic analogs of opiates and have been used for over a century, reducing the strength of pain signals as they ascend to the brain through the spinal cord.
But now that fentanyl smuggled into America has killed over a hundred thousand residents, everyone is looking for an effective alternative to opioids, and subsequently, multiple targets for pain treatment are being found. We recently discussed sodium and calcium channel targeting medications, explaining how they target pain signal-carrying neurons in the peripheral and central nervous systems, respectively, but other targets are also being found.
Pain processing takes precedence in the brain so as to avoid permanent injury or death, which is why those with chronic pain report tremendous difficulty concentrating. In times of emergency, the body also has a descending pain modification pathway so that the brain can issue signals to turn down or off pain signals from the body, allowing us to focus on something important in the environment, like running through thorns to escape a charging bear. Think of a tug of war between ascending pathways carrying pain signals and descending pathways trying to block them.
These descending pathways rely on neurotransmitters other than endorphin, and one has been found to use acetylcholine, becoming a potential new target for pain treatment. Acetylcholine is produced in the brainstem and basal forebrain and is best known for its involvement in memory, attention, and learning. Medications based on the inhibition of acetylcholine-removing enzymes in the hippocampus are currently used to treat memory problems, and the drug nicotine binds acetylcholine receptors, increasing focus and attention while producing a calming effect in some people, but no real analgesia.
The ventrolateral periaqueductal gray matter (vlPAG) is critical to these flight or flight responses, coordinating with the threat detection center of the brain, the amygdala, to react to threats and is involved in a descending pathway to blunt pain during an emergency. Pursuing a possible new treatment target, researchers published findings in the journal Neuron, indicating that the activation of cholinergic projections from the pedunculopontine tegmentum to the vlPAG has been found to relieve pain, even in opioid-tolerant conditions.
The researchers accomplished this by assaying acetylcholine actions in the vlPAG during hot and cold pain stimulation using an acetylcholine biosensor called GRAB (ACh3.0). GRAB stands for genetically encoded receptor-activated biosensor, and it utilizes genetically encoded components, like fluorescent proteins and ligand-binding domains, to detect specific molecules in living cells and measure their activity. The researchers found that inhibiting vlPAG neurons blocked pain, even in people with a high opioid tolerance, as it is working on a different pathway.
There is a long road from laboratory findings and medications being approved for use in human beings, but there is at least hope that before too long, physicians will have access to medications that work as well as opiates, without producing the euphoric or respiratory effects of opiates. However, it is important to emphasize that no medical treatment is without risk, including the decision to use no medications at all. While opponents of opioids seem to think that simply not prescribing them at all is a solution, the truth is that untreated severe chronic pain kills, and for right now, opioids are still the only effective treatment.
L. Joseph Parker is a distinguished professional with a diverse and accomplished career spanning the fields of science, military service, and medical practice. He currently serves as the chief science officer and operations officer, Advanced Research Concepts LLC, a pioneering company dedicated to propelling humanity into the realms of space exploration. At Advanced Research Concepts LLC, Dr. Parker leads a team of experts committed to developing innovative solutions for the complex challenges of space travel, including space transportation, energy storage, radiation shielding, artificial gravity, and space-related medical issues.
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