Friday, May 25, 2012
Thursday, May 24, 2012
The researchers, working with mice, focused on treating chronic pain that arises from nerve injury — so-called neuropathic pain.
In their study, published in the May 24, 2012 issue of Neuron, the scientists transplanted immature embryonic nerve cells that arise in the brain during development and used them to make up for a loss of function of specific neurons in the spinal cord that normally dampen pain signals.
A small fraction of the transplanted cells survived and matured into functioning neurons. The cells integrated into the nerve circuitry of the spinal cord, forming synapses and signaling pathways with neighboring neurons.
In this cross section of a mouse spinal cord, cells transplanted from the brain, bright green, are shown one day after injection.
As a result, pain hypersensitivity associated with nerve injury was almost completely eliminated, the researchers found, without evidence of movement disturbances that are common side effects of the currently favored drug treatment.
"Now we are working toward the possibility of potential treatments that might eliminate the source of neuropathic pain, and that may be much more effective than drugs that aim only to treat symptomatically the pain that results from chronic, painful conditions," said the senior author of the study, Allan Basbaum, PhD, chair of the Department of Anatomy at UCSF.
One month after injection the transplanted cells have dispersed within the spinal cord, near the injection site.
Although pain and hypersensitivity after injury usually resolve, in some cases they outlast the injury, creating the condition of chronic pain. Many types of chronic pain are induced by stimuli that are essentially harmless — such as light touch — but that are perceived as painful, according to Basbaum.
Chronic pain due to this type of hypersensitivity is often a debilitating medical condition. Many people suffer from chronic neuropathic pain after a bout of shingles, years or decades after the virus that causes chicken pox has been vanquished. Chronic pain is not merely prolonged acute pain, Basbaum said.
The transplanted cells grew long processes, called axons, through which they are connected to other nerve cells within the spinal cord of the host.
Those who suffer from chronic pain often get little relief, even from powerful narcotic painkillers, according to Basbaum. Gabapentin, an anticonvulsant first used to treat epilepsy, now is regarded as the most effective treatment for neuropathic pain. However, it is effective for only roughly 30 percent of patients, and even in those people it only provides about 30 percent relief of the pain, he said.
The explanation for neuropathic pain, research shows, is that following injury neurons may be lost, or central nervous system circuitry may change, in ways that are maladaptive, compromising signals that normally help dampen pain. These changes contribute to a state of hyper-excitability, enhancing the transmission of pain messages to the brain and causing normally innocuous stimuli to become painful.
This image shows the interconnectedness of the transplanted cells (green) and the neurons of the host (red). Mircrographs: Joao Braz, Neuron
The inhibitory neurons that are damaged in the spinal cord to cause pain hypersensitivity release a molecule that normally transmits inhibitory signals — the neurotransmitter GABA. A loss of GABA inhibition also is implicated in epilepsy and may play a role in Parkinson's disease. Gabapentin does not mimic GABA, but it helps to compensate for the loss of inhibition that GABA normally would provide.
Basbaum's UCSF colleagues, including study co-authorsArturo Alvarez-Buylla, PhD, and Arnold Kriegstein, MD, PhD, along with Scott Baraban, PhD, had already been experimenting with transplanting immature neurons that make GABA, using the transplanted neurons to bolster inhibitory signals in mouse models to prevent epileptic seizures and to combat a Parkinson's-like disease.
However, in those experiments the cells — which originate in a region of the forebrain known as the medial ganglionic eminence — were transplanted within the brain itself, which is their normal home.
Upon hearing about the research, Basbaum became interested in transplanting the same cells into the spinal cord as a potential treatment for the loss of GABA-driven inhibition in neuropathic pain. Success was by no means assured, as cells normally do not survive outside their natural environments within such a complex organism.
Another co-author of the Neuron study, UCSF researcher John Rubenstein, PhD, has made major progress in identifying molecules that can be manipulated to lead an embryonic stem cell to go through developmental stages that cause it to acquire the properties of GABA neurons that derive from the medial ganglionic eminence.
Pain hypersensitivity may develop following nerve injury because inhibitory nerve cells are lost in the spinal cord, increasing the likelihood of pain signals being transmitted to the brain. UCSF pain researcher Allan Basbaum, PhD, chair of the Department of Anatomy, led studies in which researchers transplanted immature inhibitory neurons from the cerebral cortex into the spinal cord, where they integrated into the host nerve circuitry and helped reverse injury-induced pain hypersensitivity. Drawings: Allan Basbaum, UCSF
According to Kriegstein, who directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, "This research is at a very early stage, and we're a long way from thinking about it in human trials, but we do have a method of making cells that are like these inhibitory neurons, starting with human embryonic stem cells."
As a step toward eventual therapies, the UCSF team plans to graft fetal human cells from the medial ganglionic eminence, or cells derived from human embryonic stem cells, into a rodent model of neuropathic pain, to see if the human cells also will alleviate neuropathic chronic pain.
"Unlike drugs, the transplanted cells can have very focused effects, depending on where they are transplanted," Kriegstein said.
According to Alvarez-Buylla, a leading scientist among those working to define the potentialities of various cells in the developing brain at different stages, "One of the amazing properties of these cells from the medial ganglionic eminence is their unprecedented migratory capacity, which enables them to navigate through multiple terrains within the central nervous system, and to then become functionally integrated with other cells. Those properties have proved useful in other places where we have transplanted them, and now in the spinal cord."
Joao Braz, PhD, an assistant research scientist, and Reza Sharif-Naieni, PhD, a postdoctoral fellow, both working in the Basbaum laboratory, carried out the bulk of the experiments published in Neuron. The authors have a patent pending on the treatment outlined in the study.
Friday, May 18, 2012
Thinking of something else is a time-honored method for coping with pain. Indeed, psychologists have demonstrated repeatedly that what you think about can modulate the pain you experience. But what's less clear is how exactly that effect plays out in the body. In a study published today in Current Biology, neuroscientists have found that distraction does more than merely divert your mind; it actually sends signals that bar pain from reaching the central nervous system.
"This study connects two important fields of pain research," says lead author Christian Sprenger, a physician and neuroscientist at the University Medical Center Hamburg–Eppendorf in Germany. "There are many studies describing the sensitization processes of the spinal cord. On the other hand, it is well known that certain psychological factors are good predictors of the development of pain."
Sprenger and his colleagues told 20 male volunteers they would be participating in an experiment that would study concentration and memory. Each subject, while undergoing functional magnetic resonance imaging (fMRI) to map their neural activity, used a computer screen to take a memory test called an "n-back test." In such a test, subjects recall a specific letter either one or two letters back from the end of a series. As initial sessions confirmed, remembering a letter two-back is more challenging than a letter one-back. Researchers gave volunteers either the one- or two-back test so that they could study the nervous system under two levels of cognitive load.
While taking the test, each subject received a burning sensation on the forearm, courtesy of a heating element that reached a little over 47 degrees Celsius—hot enough to hurt but not enough to damage the skin. After completing the test and heat stimulus session, each man rated the sensation of pain on a scale of 0 (no pain) to 100 (unbearable). On average, the amount of heat should have produced a pain level of about 60. In line with previous studies, individuals taking the tricky two-back test described less pain than those taking the simpler one-back test.
But the effect wasn't just in their heads. The fMRI revealed differences in each group taking place in their spinal cords. For those unfortunate subjects taking a one-back test, pain signals successfully reached nerve fibers along the spinal cord, creating the experience of pain. But in subjects preoccupied by the more challenging test, pain receptors were blocked. The researchers concluded that the brain sends some kind of signal to the rest of the body, which enables the nervous system to ignore most pain and focus on the task at hand.
Intrigued, the researchers decided to repeat the test but add an extra variable. As some individuals received an injection of harmless saline, others received naloxone, a drug that blocks the action of opioids. Those receiving saline showed the same pattern as before as did subjects taking a one-back test with naloxone. For subjects taking a two-back test with naloxone, however, the pain-relieving effects of a distracted brain diminished by 40 percent. The finding suggests the concentrating brain doesn't just divert attention from the agony, it also triggers a release of opioid-based compounds.
"I think this is very novel," says Tor D. Wager, a psychologist and neuroscientist at the University of Colorado at Boulder. "It has not been clear whether attention works at an output stage or modifies a higher level or even interferes with memory for pain." Wager, who is also studying the interaction of working memory and pain, explains that Sprenger's study is nearly unprecedented in its look at the spinal cord.
Sprenger and his colleagues—whose previous work examined the placebo effect—another brain–body mystery—believes distraction is just one of many cognitive cases in which the brain modulates pain. He adds that their research is a first step. Much of the pain-response process seen in this study remains unknown: current functional magnetic resonance image technology can focus on either the brain or the spinal cord, but not both, and fine details—such as precisely how naloxone interacts with the nervous system and opioids—are invisible.
The study, however, does provide a candidate mechanism for the brain's inhibition of the pain response, a mechanism that can be measured and further studied, eventually leading to clinical applications such as therapies. Meanwhile, the next time you have a toothache, rather than pop some acetaminophen, consider a brainteaser.
Thursday, May 17, 2012
Three and a half years ago, on my 62nd birthday, doctors discovered a mass on my pancreas. It turned out to be Stage 3 pancreatic cancer. I was told I would be dead in four to six months. Today I am in that rare coterie of people who have survived this long with the disease. But I did not foresee that after having dedicated myself for 40 years to a life of the law, including more than two decades as a New York State judge, my quest for ameliorative and palliative care would lead me to marijuana.
My survival has demanded an enormous price, including months of chemotherapy, radiation hell and brutal surgery. For about a year, my cancer disappeared, only to return. About a month ago, I started a new and even more debilitating course of treatment. Every other week, after receiving an IV booster of chemotherapy drugs that takes three hours, I wear a pump that slowly injects more of the drugs over the next 48 hours.
Nausea and pain are constant companions. One struggles to eat enough to stave off the dramatic weight loss that is part of this disease. Eating, one of the great pleasures of life, has now become a daily battle, with each forkful a small victory. Every drug prescribed to treat one problem leads to one or two more drugs to offset its side effects. Pain medication leads to loss of appetite and constipation. Anti-nausea medication raises glucose levels, a serious problem for me with my pancreas so compromised. Sleep, which might bring respite from the miseries of the day, becomes increasingly elusive.
Inhaled marijuana is the only medicine that gives me some relief from nausea, stimulates my appetite, and makes it easier to fall asleep. The oral synthetic substitute, Marinol, prescribed by my doctors, was useless. Rather than watch the agony of my suffering, friends have chosen, at some personal risk, to provide the substance. I find a few puffs of marijuana before dinner gives me ammunition in the battle to eat. A few more puffs at bedtime permits desperately needed sleep.
This is not a law-and-order issue; it is a medical and a human rights issue. Being treated at Memorial Sloan Kettering Cancer Center, I am receiving the absolute gold standard of medical care. But doctors cannot be expected to do what the law prohibits, even when they know it is in the best interests of their patients. When palliative care is understood as a fundamental human and medical right, marijuana for medical use should be beyond controversy.
Sixteen states already permit the legitimate clinical use of marijuana, including our neighbor New Jersey, and Connecticut is on the cusp of becoming No. 17. The New York State Legislature is now debating a bill to recognize marijuana as an effective and legitimate medicinal substance and establish a lawful framework for its use. The Assembly has passed such bills before, but they went nowhere in the State Senate. This year I hope that the outcome will be different. Cancer is a nonpartisan disease, so ubiquitous that it's impossible to imagine that there are legislators whose families have not also been touched by this scourge. It is to help all who have been affected by cancer, and those who will come after, that I now speak.
Given my position as a sitting judge still hearing cases, well-meaning friends question the wisdom of my coming out on this issue. But I recognize that fellow cancer sufferers may be unable, for a host of reasons, to give voice to our plight. It is another heartbreaking aporia in the world of cancer that the one drug that gives relief without deleterious side effects remains classified as a narcotic with no medicinal value.
Because criminalizing an effective medical technique affects the fair administration of justice, I feel obliged to speak out as both a judge and a cancer patient suffering with a fatal disease. I implore the governor and the Legislature of New York, always considered a leader among states, to join the forward and humane thinking of 16 other states and pass the medical marijuana bill this year. Medical science has not yet found a cure, but it is barbaric to deny us access to one substance that has proved to ameliorate our suffering.
Gustin L. Reichbach is a justice of the State Supreme Court in Brooklyn.
Wednesday, May 09, 2012
With deep regret and heavy hearts, we sadly inform you that due to irreparable economic circumstances, APF must cease to exist, effective immediately. On May 3, 2012, the Board of Directors formally voted to dissolve the organization.
The Board and staff have worked tirelessly over many months to address a significant gap between available financial resources and funds needed to remain operational. Unfortunately, the economic situation has not changed in any meaningful way, despite our best efforts.
APF hopes to be able to transfer content from various information, education, and support programs to other organizations so that you may continue to benefit from the value these programs have provided to thousands of individuals and families across the country.
Your personal experiences in living with pain and seeking compassion, empathy and medical care – often against the odds -- have driven our efforts over these many years. This includes enactment of key provisions of the National Pain Care Policy Act in the Health Reform Bill that led to a landmark report issued in 2011 by the Institutes of Medicine. This report documents the shocking numbers of US citizens that live with pain and calls for immediate changes to address gaps in care. Despite this, the current climate towards improving the plight of people with pain in the US continues to be precarious and hostile.
As you unfortunately know, the need for public outcry around the needs of Americans struggling with pain conditions is greater today than ever before in light of the multi-front assault occurring daily on our right to dignified care. Misguided state and federal policies are impeding access to appropriate and reasonable medical care for people struggling with pain, and deterring even the most compassionate medical providers from treating anyone with pain conditions.
It is therefore critical that each of you raise your voices singularly and together to demand the care you deserve. It is only by continuing to demand attention to the ever-worsening barriers and unacceptable suffering that change will occur.
Elected officials, policy makers, and the media need to keep hearing from each and every one of you so they are not allowed to walk away from the consequences of this over-looked public health and medical problem. Please know that although APF will cease to exist, the resolve and commitment among individuals on the Board and staff remain strong.