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Researchers Identify Brain Areas Activated by Itch-Relieving Drug

Areas of the brain that respond to reward and pleasure are linked to the ability of a drug known as butorphanol to relieve itch, according to new research led by Gil Yosipovitch, MD, Professor and Chair of the Department of Dermatology at Temple University School of Medicine (TUSM), and Director of the Temple Itch Center. The findings point to the involvement of the brain’s opioid receptors—widely known for their roles in pain, reward, and addiction—in itch relief, potentially opening up new avenues to the development of treatments for chronic itch.

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The article, published online September 11, in the Journal of Investigative Dermatology, is the first to show precisely where in the brain butorphanol works to relieve itch. In identifying those areas, the study helps to explain why butorphanol works better for chronic itching mediated by histamine, a small molecule involved in allergic reactions, than for nonhistamine-related types of itch.

"The research allows us to assess butorphanol’s effects," Dr. Yosipovitch said. "We can now identify better targets in the brain that drugs can work on to relieve itch."

The research marks an important step toward the development of itch-specific agents. As Dr. Yosipovitch explained, chronic itching, which affects roughly 12 percent of the population, comprises not just one disease, but many—ranging from atopic eczema and psoriasis to systemic diseases such as lymphoma and chronic liver failure. Biochemically, each of those diseases induces itching via one of two main pathways: one that is mediated by histamine and one that is not. Most pathological itching originates along nonhistaminergic pathways.

Working with Alexandru D. P. Papoiu, MD, PhD, at Wake Forest University School of Medicine, Dr. Yosipovitch experimentally induced itch in human volunteers using either histamine or cowhage, which incites nonhistaminergic itching. Study volunteers were then treated with either butorphanol or a placebo and subjected to functional magnetic resonance imaging (fMRI) to analyze brain activity and assess the effects of butorphanol (or placebo). When volunteers returned seven days later, they received the other treatment and again underwent fMRI.

Butorphanol suppressed histamine itching in all cases and reduced cowhage itching in 35 percent of subjects. The drug’s suppression of histamine itching was associated specifically with the activation of brain areas known as the nucleus accumbens and septal nuclei—areas located deep at the base of the forebrain. The regions are notably rich in so-called kappa (κ)-opioid receptors, on which butorphanol acts. By contrast, the relief of cowhage itch by butorphanol was linked to effects in other brain areas.

The findings suggest that butorphanol works primarily on κ-opioid receptors to suppress the itch sensation induced by histamine. But the drug also has important effects on an itch pathway that does not involve histamine, where the demand for new treatments is greatest.

How nonhistaminergic itching is reduced through the involvement of opioid receptors remains unclear. Opioid receptors modulate the transmission of information about itch in the brain and occur in high levels in the areas of the brain that house neural pathways associated with reward. Reward pathways are known particularly for their response to pleasurable stimuli. Dr. Yosipovitch and Dr. Papoiu have shown in previous work that the activation of reward circuits is correlated with pleasurability and the degree of itch relief derived from self-scratching.

The new study, which Yosipovitch carried out at Wake Forest University prior to joining the TUSM faculty in 2013, further illustrates the power of applying imaging technologies to basic questions in itch research. At Temple’s Itch Center, Yosipovitch is continuing to explore those applications.

"We are in a position now to better understand the itch-scratch cycle," he said. "To break the cycle from the top down, knowing where to target receptors in the brain, would be a major achievement."

(Source: temple.edu)

Filed under nucleus accumbens opioid receptors butorphanol itching histamine neuroscience science

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Researchers find rare genetic cause of Tourette syndrome A rare genetic mutation that disrupts production of histamine in the brain is a cause of the tics and other abnormalities of Tourette syndrome, according to new findings by Yale School of Medicine researchers. The findings, reported Jan. 8 in the journal Neuron, suggest that existing drugs that target histamine receptors in the brain might be useful in treating the disorder. Tourette syndrome afflicts up to 1% of children, and a smaller percentage of adults. “These findings give us a new window into what’s going on in the brain in people with Tourette. That’s likely to lead us to new treatments,” said Christopher Pittenger, associate professor in the psychiatry and psychology departments and in the Yale Child Study Center, and senior author of the paper. Histamine is commonly associated with allergy, but it also plays an important role as a signaling molecule in the brain. Interactions with this brain system explain why some allergy medications cause people to feel sleepy.  In 2010, Yale researchers showed that a family with nine members suffering from Tourette’s carried a mutation in a gene called HDC that disrupts the production of histamine. The new work demonstrates that this mutation causes the disorder. Mice with the same mutation develop symptoms similar to those found in Tourette’s, the Yale team showed. Also, these mice and the patients that carry the HDC mutation showed abnormalities in signaling by the neurotransmitter dopamine in parts of the brain associated with Tourette’s and related conditions. Drug companies have developed medications that target brain-specific histamine receptors in an effort to treat schizophrenia and ADHD. While not approved for general use yet, those drugs or others that target histamine receptors should be tested to see whether they can treat symptoms of Tourette syndrome, Pittenger said.

Researchers find rare genetic cause of Tourette syndrome

A rare genetic mutation that disrupts production of histamine in the brain is a cause of the tics and other abnormalities of Tourette syndrome, according to new findings by Yale School of Medicine researchers.

The findings, reported Jan. 8 in the journal Neuron, suggest that existing drugs that target histamine receptors in the brain might be useful in treating the disorder. Tourette syndrome afflicts up to 1% of children, and a smaller percentage of adults.

“These findings give us a new window into what’s going on in the brain in people with Tourette. That’s likely to lead us to new treatments,” said Christopher Pittenger, associate professor in the psychiatry and psychology departments and in the Yale Child Study Center, and senior author of the paper.

Histamine is commonly associated with allergy, but it also plays an important role as a signaling molecule in the brain. Interactions with this brain system explain why some allergy medications cause people to feel sleepy. 

In 2010, Yale researchers showed that a family with nine members suffering from Tourette’s carried a mutation in a gene called HDC that disrupts the production of histamine. The new work demonstrates that this mutation causes the disorder. Mice with the same mutation develop symptoms similar to those found in Tourette’s, the Yale team showed. Also, these mice and the patients that carry the HDC mutation showed abnormalities in signaling by the neurotransmitter dopamine in parts of the brain associated with Tourette’s and related conditions.

Drug companies have developed medications that target brain-specific histamine receptors in an effort to treat schizophrenia and ADHD. While not approved for general use yet, those drugs or others that target histamine receptors should be tested to see whether they can treat symptoms of Tourette syndrome, Pittenger said.

Filed under Tourette syndrome dopamine histamine genetics psychology neuroscience science

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Researchers find new clue to cause of human narcolepsy In 2000, researchers at the UCLA Center for Sleep Research published findings showing that people suffering from narcolepsy, a disorder characterized by uncontrollable periods of deep sleep, had 90 percent fewer neurons containing the neuropeptide hypocretin in their brains than healthy people. The study was the first to show a possible biological cause of the disorder. Subsequent work by this group and others demonstrated that hypocretin is an arousing chemical that keeps us awake and elevates both mood and alertness; the death of hypocretin cells, the researchers said, helps explain the sleepiness of narcolepsy. But it has remained unclear what kills these cells. Now the same UCLA team reports that an excess of another brain cell type — this one containing histamine — may be the cause of the loss of hypocretin cells in human narcoleptics. UCLA professor of psychiatry Jerome Siegel and colleagues report in the current online edition of the journal Annals of Neurology that people with the disorder have nearly 65 percent more brain cells containing the chemical histamine. Their research suggests that this excess of histamine cells causes the loss of hypocretin cells in human narcoleptics. Narcolepsy is a chronic disorder of the central nervous system characterized by the brain’s inability to control sleep–wake cycles. It causes sudden bouts of sleep and is often accompanied by cataplexy, an abrupt loss of voluntary muscle tone that can cause person to collapse. According to the National Institutes of Health, narcolepsy is thought to affect roughly one in every 3,000 Americans. Currently, there is no cure. Histamine is a body chemical that works as part of the immune system to kill invading cells. When the immune system goes awry, histamine can act on a person’s eyes, nose, throat, lungs, skin or gastrointestinal tract, causing the symptoms of allergy that many people are familiar with. But histamine is also present in a type of brain cell. For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep disorder center as having narcolepsy with cataplexy. These brains were also compared with the brains of three narcoleptic mouse models and to the brains of narcoleptic dogs. The researchers found that the humans with narcolepsy had an average of 64 percent more histamine neurons. Interestingly, the team did not see an increased number of these cells in any of the animal models of narcolepsy. "Humans and animals with narcolepsy share the same symptoms, but we did not see the histamine cell changes we saw in humans in the animal models we examined," said Siegel, who directs the Center for Sleep Research at the UCLA Semel Institute for Neuroscience and Human Behavior and is the senior author of the research. "We know that narcolepsy in the animal models is caused by engineered genetic changes that block hypocretin function. However, in humans, we did not know why the hypocretin cells die. "Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells," he said. The study results may also further our understanding of brain plasticity, Siegel noted. While scientists have known of the existence neurogenesis — the process by which the brain is populated with new neurons — it was thought to function mainly to replace existing cells that had died. "This paper shows for the first time that neuronal numbers can increase greatly and not just serve as replacement cells," he said. "In the current example, this appears to be pathological with the destruction of hypocretin, but in other circumstances, it may underlie recovery and learning and open new routes to treatment of a number of neurological disorders."

Researchers find new clue to cause of human narcolepsy

In 2000, researchers at the UCLA Center for Sleep Research published findings showing that people suffering from narcolepsy, a disorder characterized by uncontrollable periods of deep sleep, had 90 percent fewer neurons containing the neuropeptide hypocretin in their brains than healthy people. The study was the first to show a possible biological cause of the disorder.

Subsequent work by this group and others demonstrated that hypocretin is an arousing chemical that keeps us awake and elevates both mood and alertness; the death of hypocretin cells, the researchers said, helps explain the sleepiness of narcolepsy. But it has remained unclear what kills these cells.

Now the same UCLA team reports that an excess of another brain cell type — this one containing histamine — may be the cause of the loss of hypocretin cells in human narcoleptics.

UCLA professor of psychiatry Jerome Siegel and colleagues report in the current online edition of the journal Annals of Neurology that people with the disorder have nearly 65 percent more brain cells containing the chemical histamine. Their research suggests that this excess of histamine cells causes the loss of hypocretin cells in human narcoleptics.

Narcolepsy is a chronic disorder of the central nervous system characterized by the brain’s inability to control sleep–wake cycles. It causes sudden bouts of sleep and is often accompanied by cataplexy, an abrupt loss of voluntary muscle tone that can cause person to collapse. According to the National Institutes of Health, narcolepsy is thought to affect roughly one in every 3,000 Americans. Currently, there is no cure.

Histamine is a body chemical that works as part of the immune system to kill invading cells. When the immune system goes awry, histamine can act on a person’s eyes, nose, throat, lungs, skin or gastrointestinal tract, causing the symptoms of allergy that many people are familiar with. But histamine is also present in a type of brain cell.

For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep disorder center as having narcolepsy with cataplexy. These brains were also compared with the brains of three narcoleptic mouse models and to the brains of narcoleptic dogs.

The researchers found that the humans with narcolepsy had an average of 64 percent more histamine neurons. Interestingly, the team did not see an increased number of these cells in any of the animal models of narcolepsy.

"Humans and animals with narcolepsy share the same symptoms, but we did not see the histamine cell changes we saw in humans in the animal models we examined," said Siegel, who directs the Center for Sleep Research at the UCLA Semel Institute for Neuroscience and Human Behavior and is the senior author of the research. "We know that narcolepsy in the animal models is caused by engineered genetic changes that block hypocretin function. However, in humans, we did not know why the hypocretin cells die.

"Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells," he said.

The study results may also further our understanding of brain plasticity, Siegel noted. While scientists have known of the existence neurogenesis — the process by which the brain is populated with new neurons — it was thought to function mainly to replace existing cells that had died.

"This paper shows for the first time that neuronal numbers can increase greatly and not just serve as replacement cells," he said. "In the current example, this appears to be pathological with the destruction of hypocretin, but in other circumstances, it may underlie recovery and learning and open new routes to treatment of a number of neurological disorders."

Filed under narcolepsy histamine neurons neuroplasticity cataplexy hypocretin neuroscience science

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These scientists are ‘itching’ to help you stop scratching Itch and scratch, itch and scratch.  It’s not the most serious physical problem in our lives, but it is common and it is very annoying. Now, researchers at the Hebrew University of Jerusalem and in Boston have come up with new findings that can stop the itching through silencing the neurons that transmit itch-generating stimuli. The research was a collaborative effort by a group led by Dr. Alex Binshtok at the Hebrew University’s Department of Medical Neurobiology at the Institute of Medical Research Israel-Canada, and the Edmond & Lily Safra Center for Brain Sciences; along with Dr. Clifford Woolf’s group in the Boston Children’s Hospital and Harvard Medical School. The study demonstrated the presence of functionally distinct sets of neurons that detect and transmit itch-generating stimuli. The researchers were further able to demonstrate that they could selectively target and silence those itch-generating neurons while active. These results provide a basis for the development of novel therapeutic approaches for selective treatment of previously unmet itching not induced by histamine (non-histaminergic itch), such as dry skin itch and allergic dermatitis. (Histaminergic itch is brought on when histamine triggers an inflammatory immune response to foreign agents, such as occurs, for example, in hay fever.) The findings of the Israeli-US researchers were published in the journal Nature Neuroscience. In addition to the senior researchers, student major contributors to the project were Sagi Gudes and Felix Blasl from the Hebrew University; and David Roberson and Jared Sprague from Harvard Medical School. Itch is a complex, unpleasant, cutaneous sensation that in some respects resembles pain, yet is different in terms of its intrinsic sensory quality and the urge to scratch. Although some types of itch like urticaria (hives) could be effectively treated with anti-histaminergic agents, itch accompanying most chronic itch-inducing diseases, including atopic dermatitis (eczema), allergic itch and dry skin itch, is not predominantly induced by histamine. An understanding of the molecular and cellular mechanisms underlying the sensation of itch, therefore, is essential for the development of effective and selective treatment of itch, which in some cases could become a devastating condition, say the researchers. The researchers’ findings suggest that primary itch-generating neurons that carry messages toward the central nervous system code functionally distinct histaminergic and non-histaminergic itch pathways that could be selectively blocked. This is the first time that this has been demonstrated, and means that it is possible to block itch signals in the neurons that mediate non-histamine itch.  These findings have a great clinical importance since they could be translated into novel, selective and effective therapies for previously largely untreated dry skin itch and allergic dermatitis itch.

These scientists are ‘itching’ to help you stop scratching

Itch and scratch, itch and scratch.  It’s not the most serious physical problem in our lives, but it is common and it is very annoying. Now, researchers at the Hebrew University of Jerusalem and in Boston have come up with new findings that can stop the itching through silencing the neurons that transmit itch-generating stimuli.

The research was a collaborative effort by a group led by Dr. Alex Binshtok at the Hebrew University’s Department of Medical Neurobiology at the Institute of Medical Research Israel-Canada, and the Edmond & Lily Safra Center for Brain Sciences; along with Dr. Clifford Woolf’s group in the Boston Children’s Hospital and Harvard Medical School.

The study demonstrated the presence of functionally distinct sets of neurons that detect and transmit itch-generating stimuli. The researchers were further able to demonstrate that they could selectively target and silence those itch-generating neurons while active. These results provide a basis for the development of novel therapeutic approaches for selective treatment of previously unmet itching not induced by histamine (non-histaminergic itch), such as dry skin itch and allergic dermatitis.

(Histaminergic itch is brought on when histamine triggers an inflammatory immune response to foreign agents, such as occurs, for example, in hay fever.)

The findings of the Israeli-US researchers were published in the journal Nature Neuroscience. In addition to the senior researchers, student major contributors to the project were Sagi Gudes and Felix Blasl from the Hebrew University; and David Roberson and Jared Sprague from Harvard Medical School.

Itch is a complex, unpleasant, cutaneous sensation that in some respects resembles pain, yet is different in terms of its intrinsic sensory quality and the urge to scratch. Although some types of itch like urticaria (hives) could be effectively treated with anti-histaminergic agents, itch accompanying most chronic itch-inducing diseases, including atopic dermatitis (eczema), allergic itch and dry skin itch, is not predominantly induced by histamine. An understanding of the molecular and cellular mechanisms underlying the sensation of itch, therefore, is essential for the development of effective and selective treatment of itch, which in some cases could become a devastating condition, say the researchers.

The researchers’ findings suggest that primary itch-generating neurons that carry messages toward the central nervous system code functionally distinct histaminergic and non-histaminergic itch pathways that could be selectively blocked. This is the first time that this has been demonstrated, and means that it is possible to block itch signals in the neurons that mediate non-histamine itch. 

These findings have a great clinical importance since they could be translated into novel, selective and effective therapies for previously largely untreated dry skin itch and allergic dermatitis itch.

Filed under itch sensory neurons histamine neuroscience science

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The zebrafish revealed a central regulator for the development of the brain histamine system Research has shown that mutations in the psen1 gene are common in the familial forms of Alzheimer’s disease, and the Presenilin-1 protein that the gene encodes is known to be involved in the cleavage of the amyloid precursor protein. In Alzheimer’s disease the amyloid precursor protein is not cleaved the normal way, and the protein accumulates in the brain damaging neuronal tracts and neurons. It is still unknown if the psen1 gene is involved in the etiology of Alzheimer’s disease via another mechanism. Professor Pertti Panula’s research team at the University of Helsinki has elucidated the role of psen1 gene in the development of the neuronal histamine system and its modulation. Histamine is one of the neurotransmitters, which all are essential for cognitive functions, which in turn are impaired in Alzheimer’s disease. The histamine system is altered during the progression of Alzheimer’s disease. In the study the zebrafish was used as a model organism. The rapidly developing zebrafish is suitable as a model organism, as its transparency allows researchers to study the development and function of vital organs. To study the function of psen1 gene, zebrafish that did not produce functional Presenilin-1 protein were generated. Despite the fact that the fish lacked functional Presenilin-1 they were viable and developed until adulthood. The lack of Presenilin-1 protein induced a change in the behavior of the larval zebrafish, they did not as normal fish react to fast changes in the light intensity. “Based on previous research we know that this change in behavior is associated with lack of histamine in the brain”, Panula explains. In adulthood the motor behavior of the mutant zebrafish differed from the normal fish: the fish swam by the edges of the arena that was available and avoided the inner part. Previous studies from the group have shown that this behavioral alteration also is due to changes in the histamine system. The researchers found that larval fish lacking Presenilin-1 protein had significantly fewer histamine neurons; in adulthood the histamine neuron number was significantly increased in these fish when compared with normal fish. "These results reveal that the psen1 gene is a central regulator of the development of the histamine neurons and that the mutation can cause a persistent lifelong change in the neuronal histamine system. This is a very interesting finding", Panula states. One interesting remaining question is from where the new histamine neurons arise in the brains of adult zebrafish. Are they newly differentiated stem cells or do other cells become histamine neurons? The answer is not known, but based on these results it is advisable to elucidate the role of Presenilin-1 protein in differentiation of stem cells also in the brains of mammals. “Mammals have stem cells in the hypothalamus, in the same area where the histamine neurons are located in all studied vertebrates”, Panula comments. Panula empathizes that the published study does not tell about an Alzheimer’s disease mechanism in humans. The new knowledge on the function of psen1 gene and the development of the brain histamine system provided by the study is one step forward to understanding the etiology of the disease. "We perform basic research on molecular level, from where it is a long way to treatment of human diseases. This type of research provides the findings on which the treatments are finally based", Panula says. Journal of Neuroscience published the study that was conducted at University of Helsinki Neuroscience center, and Institute of Biomedicine. (Image: Charles Badland, Florida State University)

The zebrafish revealed a central regulator for the development of the brain histamine system

Research has shown that mutations in the psen1 gene are common in the familial forms of Alzheimer’s disease, and the Presenilin-1 protein that the gene encodes is known to be involved in the cleavage of the amyloid precursor protein. In Alzheimer’s disease the amyloid precursor protein is not cleaved the normal way, and the protein accumulates in the brain damaging neuronal tracts and neurons. It is still unknown if the psen1 gene is involved in the etiology of Alzheimer’s disease via another mechanism.

Professor Pertti Panula’s research team at the University of Helsinki has elucidated the role of psen1 gene in the development of the neuronal histamine system and its modulation. Histamine is one of the neurotransmitters, which all are essential for cognitive functions, which in turn are impaired in Alzheimer’s disease. The histamine system is altered during the progression of Alzheimer’s disease.

In the study the zebrafish was used as a model organism. The rapidly developing zebrafish is suitable as a model organism, as its transparency allows researchers to study the development and function of vital organs. To study the function of psen1 gene, zebrafish that did not produce functional Presenilin-1 protein were generated. Despite the fact that the fish lacked functional Presenilin-1 they were viable and developed until adulthood.

The lack of Presenilin-1 protein induced a change in the behavior of the larval zebrafish, they did not as normal fish react to fast changes in the light intensity. “Based on previous research we know that this change in behavior is associated with lack of histamine in the brain”, Panula explains.

In adulthood the motor behavior of the mutant zebrafish differed from the normal fish: the fish swam by the edges of the arena that was available and avoided the inner part. Previous studies from the group have shown that this behavioral alteration also is due to changes in the histamine system.

The researchers found that larval fish lacking Presenilin-1 protein had significantly fewer histamine neurons; in adulthood the histamine neuron number was significantly increased in these fish when compared with normal fish.

"These results reveal that the psen1 gene is a central regulator of the development of the histamine neurons and that the mutation can cause a persistent lifelong change in the neuronal histamine system. This is a very interesting finding", Panula states.

One interesting remaining question is from where the new histamine neurons arise in the brains of adult zebrafish. Are they newly differentiated stem cells or do other cells become histamine neurons? The answer is not known, but based on these results it is advisable to elucidate the role of Presenilin-1 protein in differentiation of stem cells also in the brains of mammals. “Mammals have stem cells in the hypothalamus, in the same area where the histamine neurons are located in all studied vertebrates”, Panula comments.

Panula empathizes that the published study does not tell about an Alzheimer’s disease mechanism in humans. The new knowledge on the function of psen1 gene and the development of the brain histamine system provided by the study is one step forward to understanding the etiology of the disease.

"We perform basic research on molecular level, from where it is a long way to treatment of human diseases. This type of research provides the findings on which the treatments are finally based", Panula says.

Journal of Neuroscience published the study that was conducted at University of Helsinki Neuroscience center, and Institute of Biomedicine.

(Image: Charles Badland, Florida State University)

Filed under amyloid precursor protein psen1 gene histamine neurotransmitters alzheimer's disease zebrafish neuroscience science

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