A New Look at an Ancient Pain Remedy
Despite legal restrictions in some states, cannabis has reemerged for its medical benefits in recent years, though its history dates back centuries.
Published April 1, 2005
By Alan Dove
Academy Contributor
While some researchers are pursuing genomic strategies to understand the causes of chronic pain, others are reversing the problem, starting with an ancient painkiller and trying to understand how it works.
Cannabis sativa and its close cousin Cannabis indica, better known as marijuana, have been used as medicinal herbs for centuries, and many patients suffering from chronic pain still use this herbal remedy today, despite its obvious drawbacks. To provide the painkilling benefits of marijuana without the side effects and legal troubles, pharmaceutical companies are now searching for more selective drugs that will use the same molecular targets.
On Oct. 26, 2004, Roger Pertwee, professor of neuropharmacology at the University of Aberdeen and an expert on pharmaceutically useful cannabinoids, gave the Academy’s Biochemical Pharmacology Discussion Group a briefing on the state of the science in this field. Marijuana contains more than 60 different cannabinoid compounds, and most are still poorly understood. These cannabinoids tap into a natural signaling system involving the body’s own endocannabinoids, which appear to control a wide range of physiological and pathological processes.
Early studies focused on a single cannabinoid, delta-9 tetrahydrocannabinol (THC), the main psychotropic ingredient of marijuana. Simple THC preparations are now prescribed to suppress nausea and stimulate appetite in cancer and HIV patients, but they are only moderately effective. A major breakthrough came in the early 1990s, with the discovery of CB1 and CB2, the receptors that bind cannabinoids in humans.
Popular in New Drug Development
CB1 and CB2 proteins are woven into the cell membrane, leaving loops of receptor protein hanging into the cell and the extracellular space. The structure is typical of receptors that act through multipurpose signaling molecules, called G proteins. G protein coupled receptors, including CB1 and CB2, are involved in a huge range of cellular responses. They also are among the most popular targets for new drug development.
CB1 is found on neurons, and stimulating it inhibits the release of neurotransmitters that communicate nerve impulses. In contrast, CB2 is seen primarily on cells of the immune system, and appears to modulate the release of cytokines that direct the immune response. Chemists have developed selective agonists that can stimulate either or both receptors.
Besides the agonists that stimulate CB1 and CB2, researchers have developed compounds that have the opposite effect. The most famous of these is Rimonabant, also known as Acomplia, a CB1-targeting drug currently being developed by Sanofi-Aventis for a variety of indications.
While the opposite of an agonist is usually called an antagonist, the story is more complicated in the cannabinoid system. A receptor antagonist blocks activation of the receptor. Rimonabant and related compounds go a step further.
“Their pharmacology is somewhat complicated,” says Pertwee. “They don’t just block. They produce effects themselves, and those effects are opposite to what you get with an agonist.”
For example, while CB1 receptor agonists inhibit neurotransmitter release, inverse agonists specifically stimulate neurotransmitter release from neurons. In animals, cannabinoid agonists act as painkillers, while Rimonabant actually amplifies pain responses. Rimonabant also exacerbates tremors and spasticity in a mouse model of multiple sclerosis (MS), whereas cannabinoid agonists reduce those symptoms.
Numerous Applications
Targeting the cannabinoid system could have numerous applications, as the investors buzzing about Rimonabant have already realized. Pertwee focuses on cannabinoid analogs’ potential uses as painkillers and as treatments for MS.
In animal models, CB1 agonists reduce acute and inflammatory pain, as well as the difficult-to-treat neuropathic pain that is untouched by traditional opioids. This aligns nicely with the patterns of CB1 expression in the nervous system, where it appears in areas of the brain and peripheral nerves involved in pain perception.
CB1 also is in the brain regions responsible for controlling movement. Satisfyingly, CB1 agonists reduce tremors and spasticity, and may even reverse the demyelination process in animal models of MS. CB2 agonists also reduce pain, including neuropathic pain. This is surprising, because CB2 is not known to be expressed on neurons.
Drug developers are now pursuing many strategies to improve the benefit-to-risk ratio for cannabinoid receptor activation in the clinic. These include targeting CB1 receptors outside the central nervous system, selectively activating CB2 receptors, and elevating endocannabinoid levels by delaying their removal from their sites of action.
Still another approach is to enhance the response of CB1 receptors to endogenously released endocannabinoids, by activating an allosteric site that Pertwee and his colleagues recently discovered on the CB1 receptor.
Meanwhile, patients suffering from chronic pain or MS continue to use marijuana and THC-containing extracts. Though this is less than ideal, Pertwee points out that when subjective reports from patients are taken into account, “My own view is that the benefits outweigh the risks.”
Also read: New Age Therapeutics: Cannabis and CBD
