A new drug aimed at treating chronic pain has shown promising results in preclinical tests in mice, and is likely to enter clinical trials if it passes further animal tests. The drug seems to work mainly in a perception-related brain region known as the anterior cingulate cortex (ACC), by helping neurons to “unlearn” their hypersensitivity to incoming pain signals.
“I think that this drug potentially can be used for spinal cord injury, cancer pain, and many of other types of neuropathic pain,” says Min Zhuo, a pain researcher at the University of Toronto and principal investigator on the new study.
The drug, which still has only a preclinical codename, NB001, aims to exploit differences between everyday acute pain, an essential steering signal for any animal, and chronic pain, which too often is merely debilitating. One of the most common medical conditions worldwide, chronic pain affects more than 76 million people in the United States alone, according to the National Centers for Health Statistics.
Researchers now understand that chronic pain can be caused not just by an ongoing pain stimulus, such as a growing tumor or an inflamed nerve-end, but also by the nervous system’s sensitization to those ongoing pain signals. If the pain signals are transmitted for too long, the nervous system “learns” to expect them, by strengthening its connections along the pain-perception pathway. Past a certain point, it seems, the system can’t easily undo this sensitizing process. In extreme cases, pain may be felt even when there are no pain signals coming in from the body, so that the pain is effectively a hallucination—though it feels real enough.
In a series of studies published over the past eight years, Zhuo and his colleagues have found that adenylyl cyclase enzymes, particularly one known as AC1, seem to be important for the formation and/or maintenance of new synapses—connections between neurons—in this pain-learning process. As the researchers reported in 2006, for example, mice that lack the AC1 gene show reduced chronic pain signs in standard tests, yet retain a normal sensitivity to acute pain.
In the current study, published in Science Translational Medicine on Jan. 12, Zhuo and his colleagues used a cell model to screen for compounds that could inhibit AC1 and thus block this pain-learning process. One of these compounds, NB001, worked well in the cell model and also powerfully reduced chronic pain signs in mice, when delivered by an injection into the body. The researchers found that it also had a potent effect when injected into the ACC, but no significant effect when injected in the spine—implying that the drug principally affects the ACC and perhaps other pain-learning neurons in the brain.
“We tested NB001 against gabapentin, one of the leading drugs approved for neuropathic pain,” says Zhuo, “and to get the same effect as the usual 50 to 100 mg/kg dose of gabapentin, we needed only 1 to 3 mg/kg of NB001.”
The drug options for people with chronic pain are not ideal. Gabapentin affects a variety of cells in the body besides neurons, has a variety of potential adverse side effects, and also shows a wide variation in how well it works on different chronic pain patients. Other drugs used for chronic pain have similar drawbacks, and opioid painkillers such as morphine can be addictive as well. “We clearly need new drugs for chronic pain,” says Allan Basbaum, a pain researcher at the University of California at San Francisco who co-authored a commentary on the Zhuo lab’s paper in the same issue of Science Translational Medicine. Basbaum also is a member of the Dana Alliance for Brain Initiatives.
In their study, Zhuo and his colleagues reported that although NB001 strongly reduced chronic pain signs in mice, it did not significantly affect acute pain sensitivity, or cause cognitive side effects such as impairments of fear memories. The researchers also noted that AC1 is expressed only in neurons, making it unlikely that an AC1-blocking drug would cause side effects outside the nervous system.
Within the nervous system, however, AC1 is expressed widely. It occurs, for example, in the hippocampus, a key memory region. Although the NB001-treated mice so far have shown no memory impairments, Basbaum says that “one has to be concerned that [in humans] there might be memory effects or other cognitive effects.” Further toxicity tests of NB001 in animals will hopefully clarify these issues, he adds.
Zhuo’s lab is now working to finish the animal tests of NB001 that are required for an FDA clinical trial application, and Zhuo hopes to find a pharmaceutical company partner to fund the development of an AC1-blocking chronic pain drug. “We now have a patent on the medical use of these [NB001-related] chemicals,” he says, “and we are actively negotiating with different companies.”