Taking Aim at Pain in the Brain
How does chronic pain start? Many researchers now believe the bulk of the blame falls on the brain. But how can we make the pain stop? When it comes to addressing that problem, most studies focus on targets in the spinal cord and peripheral nerves, and steer clear of the cerebral cortex.
A pair of recent papers may help open up the brain as a target for pain therapy. The studies, from the laboratory of Min Zhuo at the University of Toronto in Canada, take aim at pain-related synaptic plasticity in the anterior cingulate cortex (ACC), a brain region that connects the frontal cortex, amygdala, and hypothalamus, bringing together autonomic functions—including sensation—with emotion and cognition.
Zhou’s group previously showed that calcium/calmodulin-stimulated adenylyl cyclase type 1 (AC1) was required for synaptic changes in the ACC after nerve injury in mice. In a new study, they identify a small molecule inhibitor of the enzyme, and show it has analgesic effects in animals. In a separate report, they use an inhibitor of protein kinase M zeta (PKMζ), another enzyme involved in synaptic plasticity in the ACC and elsewhere, to alleviate pain hypersensitivity in a mouse model of neuropathic pain.
“This isn’t a magic bullet for all chronic pain,” Zhuo told PRF. “But for severe neuropathic pain, such as long-lasting spinal cord injury pain or cancer pain, if we can reduce the sensitization in the brain, I think we’ll be able to make patients feel better.”
The ACC is a well known participant in pain. For decades, clinicians have observed that lesions in that region, either from strokes or surgery, can selectively reduce chronic pain. More recently, functional imaging studies in humans have revealed that pain elicits a rash of activity in the ACC.
Zhuo and his colleagues previously found that peripheral nerve injury induces long-term potentiation (LTP) of ACC synapses (Wei and Zhuo, 2001) that is similar to the central sensitization that occurs in the dorsal horn of the spinal cord. That indicated that blocking LTP in the ACC might be a good target for treating persistent pain.
Unfortunately, the mechanism of pain-related LTP in the ACC turns out to be similar to LTP in the hippocampus, which underlies learning and memory. Both use NMDA receptor pathways, and as a result, targeting LTP as a pain treatment strategy runs the risk of producing cognitive problems. NMDA receptor antagonists, for example, are used as analgesics, but they are limited by cognitive and motor side effects (Chizh et al., 2001).
Zhuo’s group has been hunting for proteins downstream of the NMDA receptor that might make better targets for treating pain. Earlier, they showed that AC1 knockout mice experienced a dramatic reduction in inflammatory and neuropathic pain, but no effects on acute pain (Wei et al., 2002, Xu et al., 2008).
The group set out to find a drug with a similar effect, and their results are reported in the January 12 issue of Science Translational Medicine. By screening a small collection of rationally designed compounds, they identified NB001 as the most potent inhibitor of AC1 in cultured human cells and mouse brain slices. In mouse and rat models of neuropathic and inflammatory pain, systemic administration of the compound reduced the animals’ pain hypersensitivity. NB001 appeared to act in the brain, because it was effective when injected into the ACC, but not when applied intrathecally or subcutaneously. In normal mice, responses to noxious heat and punctate stimuli were untouched, indicating that the molecule does not meddle with acute pain responses. Treated animals also sailed though learning and memory tests, as well as tests for anxiety and motor function.
These results hint that it may be possible to target AC1 without the serious side effects that typically plague attempts to take pain treatment into the brain. Now, further studies are needed to make sure that memory processing in the hippocampus is really spared, say Reza Sharif-Naeini and Allan Basbaum of the University of California, San Francisco. Writing in an accompanying perspective, they point out that in previous studies, AC1 mutant mice showed depressed hippocampal LTP and had problems with a water maze memory test (Wu et al., 1995). “It will be essential,” they write, “to conduct a thorough examination of the effects of NB001 on hippocampal function in particular and on memory processing in general.”
In the other paper, published at the end of last year in Science, Zhuo and his collaborators reported results on another protein involved in ACC plasticity, protein kinase M zeta (PKMζ). They found that PKMζ, acting downstream of AC1, maintains the injury-induced synaptic changes that AC1 helps to create. When the researchers inhibited PKMζ with a peptide in mice, they were able to alleviate neuropathic pain. However, PKMζ is also crucial for long-term memory storage in the hippocampus and other brain regions (Sacktor, 2011). Inhibiting PKMζ to treat pain “is going to give you some side effects,” says Zhuo.
But when it comes to targeting AC1, he is very optimistic: “So far so good. We haven’t really seen anything negative.” In fact, Zhuo says he is now working to move NB001 into pre-clinical testing.
In the meantime, Zhou’s group will keep looking for other therapeutic targets in the LTP pathways of the cortex. “This is just the beginning of looking at cortical plasticity and chronic pain,” he said.
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