Build a Better Painkiller | Eurek alert!

In one look :

  • In a quest to develop more effective painkillers, scientists are studying how cannabidiol, or CBD, inhibits pain-sensing neurons
  • Recent research suggests that CBD dampens the activity of pain-sensing neurons by simultaneously blocking sodium channels and activating potassium channels.
  • The findings could inform the design of new pain therapies that harness and optimize the beneficial properties of CBD

In recent years, cannabidiol, a compound derived from cannabis plants, has started to appear more and more in everyday life. Now legal in most US 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 is praised by some for its anti-aging properties. -pain.

But does CBD actually relieve pain? If so, how exactly does it do it? And what would it take to harness the beneficial properties of CBD into a safe and effective pain reliever?

These are some of the questions that Bruce Bean, Robert Winthrop Professor of Neurobiology at Harvard Medical School’s Blavatnik Institute, and Clifford Woolf, HMS Professor of Neurology at Boston Children’s Hospital, have teamed up to explore.

Their research so far, conducted in animal models and cells, suggests that CBD acts on two targets simultaneously in pain-sensing neurons. They are now using this information to develop drugs that work similarly to CBD and are just as safe and non-addictive, but are more efficiently absorbed by the body.

Untreated pain is a significant and widespread health condition that can interfere with daily activities, lead to poor mental health, and generally result in a reduced quality of life for sufferers. The US 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 longer than three to six months.

An earlier study suggests that the economic toll of chronic pain in the United States is between $560 billion and $635 billion per year. However, some of the currently available and commonly prescribed painkillers have enormous addictive potential, leaving those who use them vulnerable to becoming addicted.

“Something that would relieve pain without being addictive is a big unmet need and remains one of modern medicine’s most daunting challenges,” Bean said.

A convergence of research

Bean and Woolf have long shared an interest in developing better painkillers. Currently, effective treatments for pain are somewhat limited, Woolf said, and opioid medications 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 that in 2021, opioids were involved in 75.1% of overdose deaths, resulting in 80,816 deaths.

Prescription opioids, while not directly implicated in most overdose deaths, often serve as a gateway to more dangerous synthetic opioids like fentanyl. Yet progress in developing new pain treatments has been slow, largely because these drugs must precisely target only pain pathways while sparing other parts of the nervous system.

“We’re both very interested in conditions for which there’s no effective treatment, and the pain certainly happens to be that,” Woolf said. “We are trying to see if we can have a big impact on patients by coming up with new classes of highly effective and safe painkillers.”

However, the researchers did not initially plan to work together on CBD.

Bean conducts fundamental research on the mechanisms underlying electrical signaling in the brain. Specifically, he studies tiny channels in the membranes of neurons that open and close to control the flow of ions, which in turn determines whether neurons fire and transmit electrical messages.

Woolf’s work centers on the discovery of new drugs to treat pain and neurodegenerative diseases. He specializes in performing large-scale screens on human neurons to identify novel drug targets, as well as compounds that modify the course of disease. In particular, he focuses on membrane receptors and ion channels that mediate inflammation and pain.

During his research, Bean was intrigued by experiments suggesting that CBD reduces pain-related behavior in mice and rats, as well as anecdotal reports of CBD as an analgesic in humans.

“There aren’t any good clinical studies on CBD for pain, but a lot of people say it helps with their pain,” Bean said. “We started looking at CBD directly at the electrical activity of neurons to see what it was doing and how it was doing it.”

Working in mouse models, Bean and his team discovered that CBD inhibits two different types of sodium channels found in the membranes of nociceptors, specialized neurons that detect and communicate pain. This inhibition prevents sodium from rushing inside the nociceptors, which keeps the neurons in an inactive state and prevents them from triggering 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 interacted with a particular potassium channel found in nociceptor membranes and was involved in suppressing the signaling of the pain – and unexpectedly they hit the CBD.

Together, Woolf and Bean found that CBD activated the potassium channel, allowing potassium ions to flow inside nociceptors. This influx of potassium reduces the firing activity of neurons, thereby blocking pain signaling. In fact, flupirtine, an analgesic with restricted use due to its liver toxicity, works by the same mechanism.

“We realized that CBD is really interesting because it actually acts on two different targets in pain-sensing neurons,” Bean said.

The dual discovery of CBD is particularly exciting, Woolf added, because sodium and potassium channels work together to modulate nociceptor activity, but there is no treatment that targets both.

“There was nothing in the literature about it, but it appeared that CBD had this potassium channel opening activity in addition to 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 CBD

CBD has several advantages as a possible basis for a possible pain medicine. More importantly, it does not appear to be addictive and it appears to be relatively safe in humans with few side effects. In fact, it’s already FDA-approved for use in children with severe, drug-resistant epilepsy.

Yet CBD is far from ready for prime time. As an herbal compound derived from cannabis plants, it is highly variable from batch to batch and may contain other ingredients with adverse effects. Children with epilepsy take CBD orally, mixed with sesame oil, and since CBD is poorly absorbed by the body in this form, they must consume large amounts. Gaps remain in understanding the safety of CBD, including how it affects various organ systems as well as how it interacts with other medications.

“CBD has features we want, but it doesn’t have exactly what we want, so we have to work to improve it,” Woolf said. “We’re trying to take this herbal compound with a profile that we think is promising and make it even better and more reliable.”

“Although CBD is very effective in blocking the activity of pain-sensing neurons when applied directly to a neuron in a dish, we have no idea what concentration ultimately reaches nerve cells in the body. , and the concentration is likely very low with oral administration,” Bean added, so CBD itself is unlikely to be useful as a pain reliever. “We want to make new compounds that retain the properties and activity we found in CBD, but are more effective drugs.”

It’s also critical, he said, that any new compound not act on CB1, the receptor that binds THC to give marijuana its psychoactive effects.

Importantly, the researchers noted, any CBD medicine would need to be rigorously tested and approved by the FDA to ensure both safety and efficacy.

Bean and Woolf take a two-pronged approach to their work. One avenue is to start with the CBD molecule itself and try to create derivatives based on this initial scaffolding that enhance 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 in pain-sensing neurons targeted by CBD.

The researchers pointed to CBD as part of their larger effort to change the way drugs, including painkillers, are developed. In traditional drug development, Woolf said, researchers choose a single target and find compounds that act on that target. However, this approach has had limited success in translating results from the lab to the clinic: when compounds move on to clinical trials, they often turn out to have poor efficacy or unexpected side effects.

“We’re trying to identify new ways to develop therapies, and we’ve recognized that an alternative strategy is a polypharmacological strategy,” Woolf said. “The idea is that multiple targets will give us greater selectivity and safety than compounds that only act on a single target.”

This strategy is bolstered by growing evidence that different types of neurons in the body have different combinations of ion channels – knowledge that researchers are trying to exploit to develop more targeted drugs with fewer side effects. CBD, for example, targets a combination of sodium and potassium channels that appears to be specific to nociceptors, which may reduce the off-target effects of the compound.

And while their CBD research is largely a work in progress, the researchers hope they will eventually succeed in developing a CBD-based medicine that is safe, effective, and easy to take — and in the process, achieve their overarching goal of building a better pain medicine.

Both Woolf and Bean received funding from the Charles R. Broderick III Phytocannabinoid Research Initiative at HMS.

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