Posts tagged morphine
Articles and news from the latest research reports.
Study identifies new drug target for chronic, touch-evoked pain
Researchers at the School of Medicine have identified a subset of nerve cells that mediates a form of chronic, touch-evoked pain called tactile allodynia, a condition that is resistant to conventional pain medication.
The discovery could point researchers to more fruitful efforts to develop effective drugs for the condition.
Touch-evoked pain occurs as part of a larger neuropathic pain condition arising from damage or disruption of nerve-cell circuits or signals caused by disorders such as alcoholism, diabetes, shingles and AIDS, or procedures such as spine surgery and chemotherapy. For patients with tactile allodynia, the slightest touch — a gentle caress or the brush of shirt against skin — can cause excruciating pain because changes in nerve-cell signals or networks trick the brain into mistaking touch for pain.
The study, published online Feb. 27 in Neuron, found that these “touch” neurons are different from the usual “pain” neurons that respond to stimuli such as cuts or bruises.
Unlike pain caused by such wounds, neuropathic pain is difficult to manage because little can be done to repair nerve damage. Managing it may require strong painkillers or combinations of treatments.
Common painkillers such as morphine have little effect on touch-evoked pain, possibly because they don’t target the touch neurons, the authors say. Morphine binds to specific protein-binding sites on pain neurons called mu opioid receptors, or MORs, and cuts off the their signals so that the brain can no longer sense pain.
However, the touch neurons do not carry MORs, which is why morphine cannot bind to them and block the pain. Instead, they carry delta opioid receptors, or DORs, whose role in pain control has been unclear until recently.
"That’s been the problem so far; any type of severe pain you have, you go into the clinic and very likely you will be treated with morphine-like opioids," said Gregory Scherrer, PharmD, PhD, the senior author of the study and an assistant professor of anesthesia. "You can give some of these patients as much morphine as you want; it won’t work if the mu opioid receptor is not present on the neurons that underlie that type of pain."
There are currently no Food and Drug Administration-approved pain-control drugs that target DORs. Previous attempts at developing DOR-targeting drugs haven’t succeeded because researchers didn’t know what type of pain such drugs would be useful for, Scherrer said.
Two DOR-binding drugs developed for knee pain by Adolor Corp., a biotechnology firm, for instance, probably failed because there is no compelling evidence that DOR was present or involved. AstraZeneca, another pharmaceutical firm, also had a DOR program but recently stopped its research efforts, Scherrer added.
"Now that we have provided a rationale and mechanism supporting the utility of DOR agonists for cutaneous pain and tactile allodynia, these companies will be able to design trials more carefully to evaluate specifically the drugs’ efficacy against touch-evoked pain," he said.
Earlier studies by Scherrer and others hinted at the presence of special nerve fibers on the skin that might contribute to touch-evoked pain.
In the current study, Scherrer and colleagues used fluorescent mouse models to isolate these neurons and identify how they control touch-evoked pain. They found that DOR can play an inhibitory role in these neurons: When proteins bind to DOR, they cut off communication to the spinal cord, through which sensory signals travel to the brain.
DOR-carrying “touch” neurons pervade the skin and could easily be targeted by drugs in the form of skin patches or topical creams, Scherrer suggested.
"By contrast, most MOR-carrying neurons penetrate internal organs," he said. "That’s why morphine is effective in treating post-surgery pain, for example."
Scherrer and fellow researchers tested two different DOR-binding compounds individually on mice and found that both reduced the mice’s sensitivity to touch-evoked pain.
Preliminary studies also indicate that DOR-targeting drugs might not cause dramatic side effects like morphine does, especially if they can be used topically, Scherrer said.
"Morphine and other MOR-targeting drugs have myriad deleterious side effects — including addiction, respiratory depression, constipation, nausea and vomiting — that further limits their utility for chronic pain management," he said.
The next step is to determine whether DOR could be a target for other types of pain, such as arthritis pain, pain from bone cancer and muscle pain, Scherrer added.
The findings also suggest that the body’s opioid system — normally associated with pain and addiction — may also respond to other stimuli such as touch.
"We may have underestimated the importance of the opioid system and what can be achieved with drugs targeting other subtypes of opioid receptors," Scherrer said.
(Source: med.stanford.edu)
The pain puzzle: Uncovering how morphine increases pain in some people
For individuals with agonizing pain, it is a cruel blow when the gold-standard medication actually causes more pain. Adults and children whose pain gets worse when treated with morphine may be closer to a solution, based on research published in the January 6 on-line edition of Nature Neuroscience.
"Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients," says senior author Dr. Yves De Koninck, Professor at Université Laval in Quebec City. The team included researchers from The Hospital for Sick Children (SickKids) in Toronto, the Institut universitaire en santé mentale de Québec, the US and Italy.
New pathway in pain management
The research not only identifies a target pathway to suppress morphine-induced pain but teases apart the pain hypersensitivity caused by morphine from tolerance to morphine, two phenomena previously considered to be caused by the same mechanisms.
"When morphine doesn’t reduce pain adequately the tendency is to increase the dosage. If a higher dosage produces pain relief, this is the classic picture of morphine tolerance, which is very well known. But sometimes increasing the morphine can, paradoxically, makes the pain worse," explains co-author Dr. Michael Salter. Dr. Salter is Senior Scientist and Head of Neurosciences & Mental Health at SickKids, Professor of Physiology at University of Toronto, and Canada Research Chair in Neuroplasticity and Pain.
"Pain experts have thought tolerance and hypersensitivity (or hyperalgesia) are simply different reflections of the same response," says Dr. De Koninck, "but we discovered that cellular and signalling processes for morphine tolerance are very different from those of morphine-induced pain."
Dr. Salter adds, “We identified specialized cells – known as microglia – in the spinal cord as the culprit behind morphine-induced pain hypersensitivity. When morphine acts on certain receptors in microglia, it triggers the cascade of events that ultimately increase, rather than decrease, activity of the pain-transmitting nerve cells.”
The researchers also identified the molecule responsible for this side effect of morphine. “It’s a protein called KCC2, which regulates the transport of chloride ions and the proper control of sensory signals to the brain,” explains Dr. De Koninck. “Morphine inhibits the activity of this protein, causing abnormal pain perception. By restoring normal KCC2 activity we could potentially prevent pain hypersensitivity.” Dr. De Koninck and researchers at Université Laval are testing new molecules capable of preserving KCC2 functions and thus preventing hyperalgesia.
The KCC2 pathway appears to apply to short-term as well as to long-term morphine administration, says Dr. De Koninck. “Thus, we have the foundation for new strategies to improve the treatment of post-operative as well as chronic pain.”
Dr. Salter adds, “Our discovery could have a major impact on individuals with various types of intractable pain, such as that associated with cancer or nerve damage, who have stopped morphine or other opiate medications because of pain hypersensitivity.”
Cost of pain
Pain has been labelled the silent health crisis, afflicting tens of millions of people worldwide. Pain has a profound negative effect on the quality of human life. Pain affects nearly all aspects of human existence, with untreated or under-treated pain being the most common cause of disability. The Canadian Pain Society estimates that chronic pain affects at least one in five Canadians and costs Canada $55-60 billion per year, including health care expenses and lost productivity.
"People with incapacitating pain may be left with no alternatives when our most powerful medications intensify their suffering," says Dr. De Koninck, who is also Director of Cellular and Molecular Neuroscience at Institut universitaire en santé mentale de Québec.
Dr. Salter adds, “Pain interferes with many aspects of an individual’s life. Too often, patients with chronic pain feel abandoned and stigmatized. Among the many burdens on individuals and their families, chronic pain is linked to increased risk of suicide. The burden of chronic pain affects children and teens as well as adults.” These risks affect individuals with many types of pain, ranging from migraine and carpel-tunnel syndrome to cancer, AIDS, diabetes, traumatic injuries, Parkinson’s disease and dozens of other conditions.
Morphine and cocaine affect reward sensation differently
A new study by scientists in the US has found that the opiate morphine and the stimulant cocaine act on the reward centers in the brain in different ways, contradicting previous theories that these types of drugs acted in the same way.
Morphine and cocaine both affect the flow of the neurotransmitter dopamine, which has been shown to be important in the feeling of reward. When a dopamine neuron is stimulated it releases dopamine, which is then taken up by neighboring cells. Any excess is reabsorbed into the original dopamine neuron by a process known as “reuptake.”
Cocaine is known to block reuptake, and the excess dopamine leads to an enhanced reward effect. Cocaine is also known to make the cells in the nucleus accumbens, which receives signals from the VTA, more sensitive to cocaine. It was already known a protein called brain-derived neurotrophic factor (BDNF) in the VTA region of the brain enhances the reward response to cocaine.
The new study shows that BDNF has the opposite effect when morphine is present, decreasing the reward response and the development of addiction rather than enhancing it. The researchers identified numerous genes regulated by BDNF and associated with its effects. They used genetic techniques to suppress BDNF, and then directly excited the neurons in the nucleus accumbens that normally receives transmitted impulses from the VTA.
They found that suppressing BDNF in the VTA allowed morphine to increase the excitability of dopamine neurons and hence enhance the reward. When they optically excited the dopamine terminals in the nucleus accumbens that normally receive the transmissions from the VTA, they also found a reversal in the normal effect of BDNF.
In a major breakthrough, an international team of scientists has proven that addiction to morphine and heroin can be blocked, while at the same time increasing pain relief.
The team from the University of Adelaide and University of Colorado has discovered the key mechanism in the body’s immune system that amplifies addiction to opioid drugs. Laboratory studies have shown that the drug (+)-naloxone will selectively block the immune-addiction response. The results - which could eventually lead to new co-formulated drugs that assist patients with severe pain, as well as helping heroin users to kick the habit - will be published in the Journal of Neuroscience.
"Our studies have shown conclusively that we can block addiction via the immune system of the brain, without targeting the brain’s wiring," says the lead author of the study, Dr Mark Hutchinson, ARC Research Fellow in the University of Adelaide’s School of Medical Sciences.
"Both the central nervous system and the immune system play important roles in creating addiction, but our studies have shown we only need to block the immune response in the brain to prevent cravings for opioid drugs."
Watch a video of Dr Mark Hutchinson talking about this study.