Researchers at the University of Michigan (MI, USA) have recently demonstrated that powerful endogenous painkillers can be released by electrically stimulating specific regions of the brain.
Investigators have been building on findings from previous studies demonstrating that electric stimulation of the brain could decrease the intensity of headache pain in patients with chronic migraine. However, the reason behind the pain decrease was unclear. Alexandre DaSilva, a coauthor of the study and director of the University of Michigan‘s Headache and Orofacial Pain Effort Laboratory, is hopeful that their new findings will help to explain why transcranial direct current stimulation (tDCS) can decrease pain, and also raise the possibility of tDCS as an alternative to pharmaceutical opiates for pain relief in the future.
In the study, a patient with trigeminal neuropathic pain, a severe type of chronic facial pain, was administered with a radiotracer and underwent tDCS in a PET scanner for 20 min. The electrodes delivering the tDCS were placed so that the stimulation would reach the motor cortex. A small dose of electricity was used, approximately 2 mA, which is a fraction of the amperage used in other electrical stimulation methods, such as electroconvulsive therapy, for the treatment of psychiatric conditions.
The study indirectly measured the local endogenous release of µ-opioid, a powerful opiate-like substance that can alter pain perception, by assessing the binding potential of µ-opioid receptors. These receptors are the main target of pharmaceutical opiates such as morphine. “This is arguably the main resource in the brain to reduce pain,” DaSilva commented. “We‘re stimulating the release of our [body‘s] own resources to provide analgesia. Instead of giving more pharmaceutical opiates, we are directly targeting and activating the same areas in the brain on which they work.”
The study revealed that the patient‘s threshold for experimental cold pain was improved by 36%; however, their clinical trigeminal neuropathic pain was not significantly improved after one session. Interestingly, as a single tDCS session was able to reduce acute pain by one-third but yielded a subclinical immediate effect on chronic trigeminal neuropathic pain, the study group speculate that repeated sessions of tDCS may be required to have a lasting effect and to overcome the neuroplastic changes associated with chronic pain.
Speaking to Pain Management, DaSilva explained “While understanding central mechanisms in migraine and other chronic pain disorders using neuroimaging is important; equally important is applying these concepts to the clinical side of science. Novel neuromodulatory techniques, such as tDCS, can directly and safely target those faulty mechanisms for research and therapeutic purposes. The preliminary evidence that motor cortex stimulation with tDCS induces the release of endogenous µ-opioid is a change of paradigm in the pain neuroscience field, as we directly investigate and modulate in vivo one of the most important analgesic mechanisms in the brain. This is crucial to determine the molecular mechanisms engaged in the persistence of pain, and the development of less empirical therapies for the patients.”
The group are continuing research into this area, with results from a study with more patients appearing to support these findings. Further research will focus on both the long-term effects of tDCS and the possibility of targeting different areas of the brain to treat a variety of chronic pain conditions.
Sources: DosSantos MF, Love TM, Martikainen IK et al. Immediate effects of tDCS on the µ-opioid system of a chronic pain patient. Front. Psychiatry doi:10.3389/fpsyt.2012.00093 (2012) (Epub ahead of print); University of Michigan press release: http://ns.umich.edu/new/releases/21053-electric-stimulation-of-brain-releases-powerful-opiate-like-painkiller
Morphine is used extensively as a pain reliever in chronic pain conditions, but it can paradoxically cause pain in some patients. Researchers at Université Laval (Québec, Canada) have discovered a pathway that can be utilized to reduce paradoxical hyperalgesia caused by pharmaceutical opiates.
“Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients,” explains Yves De Koninck, Professor at Université Laval and senior author of the study published in Nature Neuroscience. “Pain experts have thought tolerance and hypersensitivity [or hyperalgesia] are simply different reflections of the same response, but we discovered that cellular and signaling processes for morphine tolerance are very different from those of morphine-induced pain.”
The discovery that two separate mechanisms are behind tolerance to morphine and hyperalgesia caused by morphine could have important implications for the development of new strategies to combat these negative side effects of morphine treatment.
In this study, researchers identified microglia in the spinal cord as potential targets for future treatments to counteract morphine-induced hyperalgesia. Michael Salter, coauthor of the study and Head of Neurosciences & Mental Health at The Hospital for Sick Children (Toronto, Canada), commented, “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 protein found to be responsible for morphine-induced hyperalgesia, KCC2, controls sensory signals to the brain by regulating the transport of chloride ions. Findings from this research have demonstrated that morphine interferes with the proper functioning of KCC2. The abnormal pain perception this causes can be reversed, without affecting the desired analgesic effect of morphine, by restoring the normal activity of KCC2.
Researchers at Université Laval are now trying to identify molecules capable of preserving the function of KCC2, in the hope of developing a novel therapy to prevent hyperalgesia. They are hopeful that manipulation of the P2X4–BDNF–KCC2 pathway could be the basis for new strategies to reduce hypersensitivity without adversely affecting morphine-induced analgesia in a variety of different pain states.
“Pain interferes with many aspects of an individual‘s life,” Salter concludes “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.”
Sources: Ferrini F, Trang T, Mattioli TA et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat. Neurosci. 16(2), 183–192 (2013); Université Laval Press Release: www.eurekalert.org/pub_releases/2013–2001/ul-tpp010313.php
A team of scientists from Rush University Medical Center and Northwestern University (IL, USA) have discovered a molecular mechanism that appears to play a key role in establishing osteoarthritis (OA) pain.
Anne-Marie Malfait, study leader and associate professor of biochemistry and of internal medicine at Rush University Medical Center, explained the reason for their research, “Clinically, scientists have focused on trying to understand how cartilage and joints degenerate in [OA]. But no one knows why it hurts.”
In a healthy individual, cartilage is one of the many parts of a joint that allows for the smooth and pain-free movement of the joint. The breakdown of cartilage in the joints of OA patients can cause stiffness, loss of movement and pain. Although this chronic condition is relatively common, and a leading cause of chronic pain, treatment options are often inadequate leading to a need for surgical intervention.
Pain associated with OA is most often brought on by physical activity and can be relieved by rest, although pain may persist during rest in the later stages of the disease due to extensive structural damage. As OA has a clear mechanical component, in that pain is often triggered by movement, researchers speculated about which mechanisms and molecules may be behind how the disease causes pain.
The study group used a mouse model to mimic the chronic development of OA over an extended period of time, during which they could monitor both pain behaviors and molecular events occurring in the knee joints and dorsal root ganglia nerves. “This method essentially provides us with a longitudinal ‘read-out‘ of the development of OA pain and pain-related behaviors in a mouse model” explained Malfait.
A specific chemokine, MCP-1, and its receptor, CCR2, were identified as being critical in the development of OA-associated knee pain. The combination of MCP-1 and CCR2 has previously been implicated in the development of pain following nerve injury, as MCP-1 can regulate the infiltration of monocytes into surrounding tissues.
Researchers observed that after a peak in MCP-1 and CCR2 levels, dorsal root ganglia signaling increased and the mice began to demonstrate movement-provoked pain behaviors, mimicking OA-associated pain. However, as Ccr2 knockout mice did not experience macrophage infiltration of the dorsal root ganglia, they were found to be much more active and did not develop movement-provoked pain behaviors, despite having the same level of structural damage as normal mice.
Furthermore, when a CCR2 receptor blocker was administered to normal mice, which had begun to demonstrate movement-provoked pain behaviors, researchers found that they became more active. However, in later stage mice the researchers found that MCP-1 and CCR2 levels had all but returned to normal, suggesting that the involvement of MCP-1 and CCR2 are implicated in the initiation, but not the long-term maintenance, of OA-associated pain.
Professor and chairman of orthopedic surgery at Rush University Medical Center, Joshua Jacobs, looked to the future of OA research “This is an important contribution to the field of [OA] research. Rather than looking at the cartilage breakdown pathway in [OA], Dr Malfait and her colleagues are looking at the pain pathway, and this can take OA research into a novel direction that can lead to new pain remedies in the future.”
Sources: Miller RE, Tran PB, Das R et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc. Natl Acad. Sci. USA 109(50), 20602–20607 (2012); Rush University Medical Center press release: www.rush.edu/webapps/MEDREL/servlet/NewsRelease?id=1644
Researchers at Stanford University School of Medicine (CA, USA) have developed a way of analyzing brain structure using computer algorithms to predict chronic lower back pain (cLBP). This could be the first step toward an objective method of diagnosing chronic pain.
Currently, the only method of measuring pain is highly subjective and relies on the patient self-reporting how much pain they are in. The possibility of using an objective method, such as neuroimaging, as a way to diagnose and measure chronic pain is particularly desirable in cases where patients find it difficult to communicate, including young children.
“People have been looking for an objective pain detector – a ‘pain scanner‘ – for a long time,” explained Sean Mackey, chief of the Division of Pain Medicine at Stanford University School of Medicine. “We‘re still a long way from that, but this method may someday augment self-reporting as the primary way of determining whether a patient is in chronic pain.”
A previous study using MRI scans accurately predicted whether participants were experiencing thermal pain in 81% of cases. This new study was designed to see whether the same method could be used to differentiate between patients with cLBP and healthy individuals.
As cLBP has been associated with abnormal brain structure, MRI scans were taken of 47 cLBP patients and 47 healthy volunteers to assess structural changes and pathological differences in their brains. A linear support vector machine was ‘taught‘ about healthy and abnormal brain structures, particularly gray matter densities in somatosensory, motor and prefrontal cortices. The machine was then able to apply what it had ‘learnt‘ to successfully predict which individuals were suffering with cLBP when reading new brain scans in 76% of cases.
The research team hopes to carry out further research in this area since their results suggest structural changes in pain-associated areas of the brain can be used to indicate the presence of a chronic pain state.
Hoameng Ung, the first author of the study and former research assistant at Stanford University School of Medicine, said, “Previous studies have shown that there are functional changes in the brain of a chronic pain patient, and we show that structural changes may be used to differentiate between those with cLBP and those without. This observation also suggests a role of the [CNS] in chronic pain, and that some types of chronic low back pain may reflect pathology not within the back, but instead within the brain.”
Sources: Ung H, Brown JE, Johnson KA, Younger J, Hush J, Mackey S. Multivariate classification of structural MRI data detects chronic low back pain. Cereb. Cortex doi:10.1093/cercor/bhs378 (2012) (Epub ahead of print); Stanford University School of Medicine press release: http://med.stanford.edu/ism/2012/december/back-pain.html
In a new study carried out at Oxford University (Oxford, UK), researchers have shown that the psychoactive constituent of cannabis has the ability to affect areas of the brain that can make pain feel less unpleasant.
Cannabis can be used in patients suffering from long-term pain who have been unable to control their pain with other drugs. The pain relief caused by cannabis has been attributed to δ-9-tetrahydrocannabinol (THC), a psychotropic agent found in cannabis. In this small-scale study published in Pain, THC does not appear to reduce the intensity of pain, unlike opiates, but instead it is able to make pain more bearable.
However, not all individuals experience the same level of pain relief when using cannabis. “Cannabis does not seem to act like a conventional pain medicine. Some people respond really well, others not at all, or even poorly,” commented Michael Lee from the Centre for Functional Magnetic Resonance Imaging of the Brain at Oxford University. He goes on to state “Brain imaging shows little reduction in the brain regions that code for the sensation of pain, which is what we tend to see with drugs such as opiates. Instead cannabis appears to mainly affect the emotional reaction to pain in a highly variable way.”
In the study, 12 volunteers were given a 15-mg oral tablet of THC or placebo, and pain was induced by the cutaneous application of a cream containing capsaicin, to produce a painful burning sensation, or a dummy cream. The participants then underwent four MRI scans, covering each of the combinations of drug and cream.
Lee explains, “The participants were asked to report the intensity and unpleasantness of the pain: how much it burned and how much it bothered them. We found that with THC, on average people did not report any change in the burn, but the pain bothered them less.”
The difference in response between individuals varied greatly, to the extent that out of the 12 volunteers tested, only six reported a change in the degree to which the pain bothered them.
However, the MRI results showed that in individuals who did report a reduction in pain unpleasantness, there was a corresponding significant suppression of activity in the anterior mid-cingulate cortex, and changes in activity of the right amygdala. These structures have previously been associated with the emotional aspects of pain.
In addition, the sensory–limbic functional connection, between the amygdala and the primary sensorimotor area, was found to be strongest in patients who demonstrated a greater degree of pain relief with THC. This may open new possibilities into understanding why some patients could benefit more from cannabis-based pain relief than others, although further research would be required to investigate this.
Lee concluded: “My view is the findings are of interest scientifically, but it remains to see how they impact the debate about use of cannabis-based medicines. Understanding cannabis‘ effects on clinical outcomes, or the quality of life of those suffering chronic pain, would need research in patients over long time periods.”
Sources: Lee MC, Ploner M, Wiech K et al. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. Pain 154(1), 124–134 (2013); Oxford University press release: www.ox.ac.uk/media/news_stories/2012/121221.html
–All stories written by Sophie Breeze