People with chronic pain are increasingly turning to medical marijuana in search of relief. And research is providing mounting evidence that compounds found in the marijuana plant, Cannabis sativa, can ease pain (see RELIEF related feature). But inhaling or ingesting marijuana produces a range of psychoactive side effects that deter many people from using it.
But recently, researchers have found a way to boost the pain-dampening power of endocannabinoids—the brain’s own natural marijuana-like signaling molecules that fight pain resulting from injury—without side effects in mice.
The work was led by Andrea Hohmann, Indiana University, Bloomington, US, who presented her findings at the 2016 annual meeting of the Society for Neuroscience (SfN), held November 12-16, 2016 in San Diego. SfN is the world’s largest neuroscience conference for scientists and physicians seeking to understand the brain and nervous system.
Location, location, location
Cannabinoids—a term that includes ingredients found in the marijuana plant, synthetically manufactured versions of them, and those made naturally by the brain—all produce their effects by associating with their receptors, which are proteins found in nerve and brain cells.
One type of cannabinoid receptor is called CB1. Tetrahydrocannabinol (THC), the main ingredient in marijuana responsible for the drug’s psychoactive effects, works by binding to and activating CB1 receptors. THC and the body’s own endocannabinoids bind to a particular location at the CB1 receptor called the “classical” binding site.
But CB1 receptors also possess an “allosteric” binding site. This is a region of the receptor where other molecules can influence how long cannabinoids stay associated with CB1. Drugs called positive allosteric modulators (PAMs), which bind to the allosteric site, cause CB1 receptors to hold on to cannabinoids for a longer period of time, boosting the activity of the receptors. The more that the receptors are active, the more opportunity there is to achieve pain relief.
Hohmann’s team took aim at the allosteric site in hopes of finding a drug that could quell pain without inducing a marijuana-like high.
Testing the new approach
Many people treated with chemotherapy for cancer develop a form of nerve injury pain called chemotherapy-induced peripheral neuropathy (CIPN). To test their new strategy, the researchers treated mice with paclitaxel, a chemotherapy drug that produces pain sensitivity similar to that seen in people with CIPN. As expected, the mice became hypersensitive to cold temperature and to touch.
But when Hohmann and her colleagues treated the mice with a PAM drug, which boosted the potency of endogenous cannabinoids, this pain sensitivity was reversed.
And, unlike marijuana itself or opioid drugs, which require increasing doses over time to achieve the same level of pain relief, the PAM remained effective at low doses. That finding suggests that a PAM would have little potential for abuse.
The PAM also failed to produce side effects commonly seen with THC, including reduced movement and body temperature. This indicated that the drug indeed acted at CB1’s allosteric site and did not activate the receptors’ classical site directly. That ensures that the PAM would affect only those brain areas where CB1 receptors are already activated by endocannabinoids, such as during chronic pain. This is in contrast to marijuana, which activates CB1 receptors throughout the body and brain, leading to side effects that also involve cognition, emotion and arousal.
Medical—and even recreational—marijuana is rapidly becoming legal in the US, and chronic pain patients are increasingly seeking out cannabinoids as treatment. But legalization has far outpaced research, leaving doctors and patients in the dark when it comes to the best way to use cannabinoids to treat pain. That’s because the US Drug Enforcement Agency (DEA) continues to classify cannabinoids—even those without psychoactive effects or abuse potential—as “Schedule 1” drugs, the same restriction placed on heroin. That sets up a huge barrier for researchers, and slows the progress of cannabinoid painkillers for use in patients. –Stephani Sutherland
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.