Summary: Cannabidiol (CBD) acts simultaneously on two targets of pain-sensitive neurons. Researchers are developing new drugs that have CBD-like actions that can be better absorbed by the body.
Source: Harvard
In recent years, cannabidiol, a compound derived from cannabis plants, has begun to appear more and more in everyday life.
Now legal in most U.S. states, the cannabinoid commonly known as CBD can be found in supermarkets and pharmacies, where it is often sold as a gum, oil, or cream, and some are praised for its suppressing properties. the pain.
But does CBD really relieve pain? If so, how accurately does it do it? And what would it take to harness the beneficial properties of CBD in a safe and effective pain medication?
These are some of the questions that Bruce Bean, professor of neurobiology Robert Winthrop at the Blavatnik Institute at Harvard Medical School, and Clifford Woolf, professor of neurology at HMS at Boston Children’s Hospital, have joined. to explore.
His research to date, in animal and cell models, suggests that CBD acts simultaneously on two targets in pain-sensitive neurons. They are now using this information to develop drugs that work in the same way as CBD and are equally safe and non-addictive, but which the body absorbs more effectively.
Untreated pain is a major and widespread health problem that can interfere with daily activities, lead to poor mental health, and generally lead to a reduction in the quality of life of those affected. The U.S. Centers for Disease Control and Prevention estimates that about 20.4% of American adults, or 50 million people, suffer from chronic pain, defined as pain that lasts more than three to six months.
An earlier study suggests that the economic cost of chronic pain in the United States is between $ 560 and $ 635 billion annually. However, some of the pain medications currently available and commonly prescribed have enormous addictive potential, so those who use them are vulnerable to becoming addicted.
“Something that would relieve non-addictive pain is a great unmet need and remains one of the most formidable challenges in modern medicine,” Bean said.
A convergence of research
Bean and Woolf have long shared an interest in developing better pain medications. Currently, effective treatments for pain are somewhat limited, Woolf said, and opioid-based drugs prescribed for pain carry a significant risk of addiction, contributing in part to the widespread opioid crisis.
In fact, the CDC estimates that since 1999, more than 932,000 people have died from drug overdoses, and by 2021, opioids were involved in 75.1 percent of overdose deaths, causing 80,816 lives. .
Prescription opioids, although not directly involved in most overdose deaths, often serve as a gateway to more dangerous synthetic opioids such as fentanyl. However, progress in developing new treatments for pain has been slow, in large part because these drugs only need to be precisely targeted to the pain pathways while saving other parts of the nervous system.
“We’re both very interested in conditions for which there is no effective treatment, and certainly the pain is that,” Woolf said.
“We’re trying to see if we can make a big impact on patients by creating new classes of highly effective and safe painkillers.”
However, the researchers initially had no plans to work together on CBD.
Bean conducts basic research on the mechanisms underlying electrical signaling in the brain. Specifically, it studies small channels in the membranes of neurons that open and close to control ion flow, which in turn determines whether neurons ignite and transmit electrical messages.
Woolf’s work focuses on discovering new drugs to treat pain and neurodegenerative diseases. He specializes in making large-scale displays in human neurons to identify new drug targets, as well as compounds that modify the course of the disease. In particular, it focuses on membrane receptors and ion channels that mediate inflammation and pain.
In the course of his research, Bean was intrigued by experiments that suggest that CBD reduces pain-related behavior in mice and rats, as well as anecdotal reports of CBD as an analgesic in humans.
“There are no good clinical studies of CBD for pain, but a lot of people say it helps them with their pain,” Bean said. “We started looking at CBD directly about the electrical activity of neurons to see what it was doing and how it was doing it.”
Working on mouse models, Bean and his team found that CBD inhibits two different types of sodium channels found in the membranes of nociceptors, the specialized neurons that sense and communicate pain.
This inhibition prevents sodium from rushing inside the nociceptors, which keeps the neurons in an inactive state and prevents them from firing and transmitting a “pain” message via an electrical signal.
Meanwhile, Woolf and his lab had screened thousands of bioactive compounds to see if any of them interact with a particular potassium channel that is found in the membranes of nociceptors and is involved in suppressing pain signaling and , unexpectedly, they hit the CBD.
Together, Woolf and Bean discovered that CBD activates the potassium channel, allowing potassium ions to flow within nociceptors. This influx of potassium reduces the firing activity of neurons, thus blocking pain signaling. In fact, flupirtine, a pain medication restricted to use due to liver toxicity, works by the same mechanism.
“We realized that CBD is really interesting because it actually acts on two different targets in pain-sensitive neurons,” Bean said.
The dual finding of CBD is especially exciting, Woolf added, because sodium channels and potassium channels work together to modulate nociceptor activity, but there are no treatments that target both.
“There was nothing in the literature about it, but it emerged that CBD had this potassium channel opening activity in addition to the sodium channel blocking activity,” Woolf said. “That’s exactly what we want if we want to control the excitability of this set of neurons.”
The future of the CBD
CBD has several advantages as a possible basis for a possible pain medication. Most importantly, it does not appear to be addictive and appears to be relatively safe in humans, with few side effects. In fact, it is already approved by the FDA for use in children with severe and drug-resistant epilepsy.
Still, the CBD is far from ready for prime time. As a compound of herbs derived from cannabis plants, it is highly variable from one batch to another and may contain other ingredients with undesirable effects. Children with epilepsy take CBD orally, mixed with sesame oil, and because CBD is poorly absorbed by the body in this form, they should consume large amounts of it.
There are shortcomings in understanding the safety of CBD, including how it affects various organ systems and how it interacts with other drugs.
“CBD has characteristics we want, but it doesn’t have exactly what we want, so we have to work to improve it,” Woolf said.
“We are trying to take this herbal compound with a profile that we believe is promising and make it even better and more reliable.”
“While CBD is very effective in blocking the activity of pain-sensitive neurons when applied directly to a neuron on a plate, we have no idea what concentration it eventually reaches the body’s nerve cells, and the concentration is likely to be very low with oral administration, ”Bean added, so CBD itself is unlikely to be useful as an analgesic.
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“We want to make new compounds that retain the properties and activity we found in CBD, but that are more effective drugs.”
It is also essential, he said, that no new compound act on CB1, the receptor that binds to THC to give marijuana its psychoactive effects.
It is important to note that, the researchers noted, any CBD-based drug should be rigorously tested and approved by the FDA to ensure safety and efficacy.
But does CBD really relieve pain? The image is in the public domain
Bean and Woolf are taking a dual approach to their work. One way is to start with the CBD molecule itself and try to create derivatives based on this initial scaffold that improve the properties of the compound.
They also plan to use large-scale screens to identify new compounds with completely different chemistry that target the same sodium and potassium channels to CBD-targeted pain-sensitive neurons.
The researchers emphasized that CBD is part of its broader push to change the way drugs, including painkillers, are developed. In the development of traditional drugs, Woolf said, researchers choose a single target and find compounds that act on that target.
However, this approach has had limited success in translating laboratory results into clinical practice: when compounds are switched to clinical trials, they often turn out to have little efficacy or unexpected side effects.
“We are trying to identify new ways to develop therapeutics and we have recognized that an alternative strategy is polypharmacological,” Woolf said. “The idea is that multiple targets will give us greater selectivity and security than compounds that only act on one target.”
This strategy is reinforced by the growing evidence that different types of neurons in the body have different combinations of ion channels, the knowledge that researchers are trying to exploit to develop more specific drugs with fewer side effects. CBD, for example, targets a combination of sodium and potassium channels that appear to be specific for nociceptors, which can reduce effects outside the target of the compound.
And while their research on CBD is largely ongoing work, researchers hope they will eventually be able to develop a CBD-based drug that is safe, effective, and easy to take and, in the process, achieve. their overall goal is to build better pain medicine.
About this pain and research news in neuropharmacology
Author: Press Office
Source: Harvard
Contact: Press Office – Harvard
Image: The image is in the public domain
Original research: Open Access.
“Cannabidiol activates Kv7 neuronal channels” by Han-Xiong Bear Zhang et al. eLife
Summary
Cannabidiol activates Kv7 neuronal channels
Cannabidiol (CBD), a chemical found in the Cannabis sativa plant, is a clinically effective antiepileptic drug whose mechanism of action is unknown. Using a fluorescence-based thallium flux assay, we performed a large-scale display and found an improvement in flux using human Kv7.2 / 7.3 channels expressed heterologously by CBD.
Patch-clamp recordings showed that CBD acts at submicromolar concentrations to change the voltage dependence of Kv7.2 / 7.3 channels in the hyperpolarizing direction, producing a dramatic improvement in current at voltages close to -50 mV. CBD improved native M current in the upper cervical ganglion of mice from 30 nM concentrations and also improved M current in rat hippocampal neurons.
The potent improvement of Kv2 / 7.3 channels by CBD may contribute to its efficacy as an antiepileptic drug by reducing neuronal hyperexcitability.
