Insight Into The Way Pain Is Regulated In The Brain Could Lead To New Target For Therapy

A UCSF-led team has demonstrated that the cerebral cortex, the site of higher cognitive functions, not only perceives pain, but plays a role in regulating pain, and that it does so in part through the inhibitory neurotransmitter GABA, suggesting a possible target for therapy.

The finding, published in the July 17 issue of Nature, provides some of the first neuroanatomical evidence that the cerebral cortex not only receives pain signals from nerve cells in lower regions of the brain, but modulates pain signals.

"Our finding suggests that the cerebral cortex is not just the end-point of pain processing. The activity of the cortex can change the set-point of the pain threshold in a top-down manner, completely modifying the experience of pain," says lead author Luc Jasmin, MD, PhD, FRCS, UCSF assistant professor of neurological surgery.

Traditionally, pain researchers have focused their research on the lower portion of the nervous system, as pain signals originate in the periphery - i.e., in the skin and other organs - and are transmitted into the spinal cord before being relayed to the brain. Intercepting pain signals at this early stage theoretically should prove effective in treating pain conditions.

However, the causes of many forms of chronic pain have proven elusive and the pain difficult to treat. In recent years, scientists have found that stimulating the cerebral cortex diminishes pain in patients with some forms of chronic pain, such as post-stroke pain syndromes, but they have not known how the relief occurs.

In the current study, conducted in normal rats, the scientists sought insight into this phenomenon by focusing on a small region of the cerebral cortex known as the rostral agranular insular cortex (RAIC), one of the few cortical areas consistently activated by painful stimuli. As GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter, or neurochemical messenger, of the brain, is prolific in the RAIC, the scientists reasoned that manipulating levels of the neurotransmitter could shed light on the way in which the RAIC might modulate pain.

The results were dramatic. When the scientists increased levels of GABA throughout the RAIC -- either by slowing the neurochemical's normal metabolism until it accumulated over hours or by expressing a gene (GAD 67) that encodes an enzyme that synthesizes GABA -- the animals displayed a clear and consistent analgesia (insensitivity to pain), as seen in the fact that they did not withdraw their paws from a hot surface. When the increase in GABA was sustained by injecting the GAD 67 gene in neuronal and glial cells (i.e., gene therapy), the animals showed analgesia up to 10 days, suggesting that GABA works through neural mechanisms that do not down-regulate over time.

Moreover, when the scientists blocked transmission of signals through the descending pain inhibitory system, which extends from the RAIC to the spinal cord, the analgesic effect was reversed, indicating that GABA worked at least in part through this system to enhance the inhibition of the neurons that incited pain.

The investigators subsequently determined that when GABA acted through the descending pain inhibitory system it worked through neurons that have GABA-A receptors and that project to a region of the brain stem known as the locus coeruleus.

But they also determined that a large number of RAIC neurons expressing GABA-B receptors project to a brain region known as the amygdala, a site involved in pain, fear and attention processes, and this led them to explore the role that GABA might have in this pathway. The results were notable. After increasing GABA in the RAIC, the scientists selectively disinhibited GABA-B bearing RAIC neurons that projected to the amygdala. As a result, the animals experienced pain. When the activation was reversed, the pain was abolished, indicating that the neural projections from the RAIC to the amygdala play a key role in initiating pain.

"This finding demonstrates that the change in pain level works through two separate systems, with opposite effects. If the activity of the locus coeruleus is increased, analgesia occurs. If the activity of the amygdala is increased, pain occurs," says senior author Peter O'Hara, PhD, UCSF associate professor of anatomy. "This dual effect is probably a defining feature of pain modulation, and we speculate that an imbalance in the cortical output is likely to underlay some chronic pain states."

In chronic pain patients, the pathway from the RAIC to the amygdala is more likely to be the one disregulated, says Jasmin, because the one from the RAIC to the locus coeruleus appears to be involved only in the response to an acute stimulus delivered over the course of a few minutes.

The rats in the study showed less pain when GABA was increased due to their decreased perception of the stimulus and their diminished fear of it.

But Jasmin says that it is also possible that the animals were simply paying less attention to the painful stimuli, a phenomenon that has been reported in humans. One study he cites demonstrated that Israeli children who were receiving dialysis for their diabetes reported less discomfort when they were watching TV.

"We know that pain perception can be altered by mood, attention and cognition, but we know little of the neural mechanisms underlying cortical modulation of pain," says Jasmin.

In upcoming work, Jasmin and O'Hara will examine the impact of GABA delivery to the RAIC on the pain threshold of rats with chronic pain conditions such as chronic inflammation, as occurs in rheumatoid arthritis, and chronic nerve injury, as occurs from diabetes and shingles. The team will examine whether sustained expression of the GAD gene in the RAIC will produce prolonged analgesia. They also will look specifically at the impact of GABA on the amygdala, and whether it changes the animals' alertness to sensory stimuli, i.e., a hot surface.

In the future, predicts Jasmin, gene therapy to increase levels of GABA in various areas of the brain will be used to treat pain, Parkinson's disease and epileptic seizures.

Co-authors of the study were Samuel D. Rabkin, Department of Neurosurgery, Massachusetts General Hospital, Boston; Albeto Granato, Department of Psychology, Catholic University, Milan, Italy; and Abdennacer Boudah, Department of Neurosurgery, UCSF.

The study was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke and the Koret Foundation.

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