Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Insight into the way pain is regulated in the brain could lead to new target for therapy

17.07.2003


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.

Jennifer O’Brien | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Health and Medicine:

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Molecular libraries for organic light-emitting diodes

24.04.2017 | Life Sciences

Research sheds new light on forces that threaten sensitive coastlines

24.04.2017 | Earth Sciences

Making lightweight construction suitable for series production

24.04.2017 | Machine Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>