Pain Management

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Fighting pain through knowledge about sensory organs in the fingertips

Jianguo Gu, University of Alabama at Birmingham


Jianguo Gu . CREDIT UAB

That a finger can distinguish the texture of satin from suede is an exquisite sensory discrimination largely relying on small sensory organs in the fingertips called Merkel discs. Jianguo Gu, Ph.D., of the University of Alabama at Birmingham, has now unraveled how the sensory information is processed in the Merkel discs and further conveyed to the ending of a sensory nerve, the start of its journey to the brain.

Such molecular understanding about the sensory information transmission between Merkel cells and nerve endings may lay the foundation to treat the intense pain felt by patients with a gentle touch of their inflamed skin — a pathological pain known as tactile allodynia. This knowledge may also point to how diabetes patients lose their sense of touch. And this new knowledge may lead to preventive care.

“Cancer patients often have touch-induced pain after chemotherapy,” said Gu, the Edward A. Ernst, M.D., Endowed Professor in the UAB Department of Anesthesiology and Perioperative Medicine. “Touch-induced pain is also commonly seen in clinical conditions such as fibromyalgia, traumatic injury and in inflammation from sunburn. Our new findings may have profound implications in these conditions.”

A Merkel disc consists of a Merkel cell and a closely associated nerve ending that branches from a single sensory nerve. Until recently, it was unclear how the physical pressure of a light touch gets transduced from a mechanical force to an electrical nerve signal in Merkel discs.

In 2014, Gu’s research team overturned the common assumption that transduction from the mechanical force takes place at the endings of the sensory nerves in Merkel discs. Instead, as he reported in the journal Cell, that mechanical transduction at Merkel discs initiates primarily in the Merkel cells. His team further pinpointed that a new ion channel in the Merkel cells — called Piezo2 — is the mechanical transducing molecule.

Now Gu and colleagues have discovered how the signal transduced by Piezo2 is passed from the Merkel cells to the nerve endings. They report in Proceedings of the National Academy of Sciences that the Piezo2 transducer triggers Merkel cells to release the neurotransmitter serotonin. This serotonin crosses the tiny gap to the nerve ending, where it activates 5-HT receptors and triggers nerve impulses.

Such gaps from one nerve cell to the next are called synapses, and they are conventional in neural communication. The newly discovered Merkel cell-nerve ending synapse is unique, Gu says, “because it is the only example of a synapse formed between a non-neuronal cell and a nerve cell, and it is the first synapse that is found underneath the skin.”

Other types of sensory nerves from the skin — which detect sensations like heat, cold or pain — have their first synapse at the point where the sensory nerve meets the spinal column.

Elucidation of a Merkel disc serotonin synapse in the skin opens several areas for future investigation.

“The serotonergic transmission in the epidermis, probably like that in the central nervous system, can be regulated by factors affecting serotonin uptake and release,” Gu and colleagues write in their PNAS paper.

“This raises an interesting issue as to whether serotonin uptake inhibitors, such as cocaine, methamphetamine and other recreational drugs in this category, may act at the epidermal serotonergic synapses to alter tactile sensations. It would also be interesting to know whether the epidermal serotonergic transmission may be altered under pathological conditions in patients with diabetes, tissue inflammation and undergoing chemotherapy, because tactile dysfunctions including mechanical allodynia and reduced tactile sensitivity are commonly observed in these patients.”

In humans and other primates, Merkel discs are concentrated in the fingertips, and lesser numbers are also found in other areas of the skin.

“They can sense the wind blowing on your skin,” Gu said.

Intriguingly, Merkel discs in nonprimate mammals are concentrated in whisker hair follicles at the base of their whisker hairs. Thus, a mouse whisker can act as a model for a human fingertip.

“Nonprimate animals can use their whiskers to sense texture, shape and other physical properties of an object,” Gu said. “A manatee has whiskers over its entire body. Bats have whiskers, too, to detect aerodynamic changes in flight.”

Posted on Pain Management

Researchers find new clues in the brain linking pain and food

Plant based food
Plant based food


It has long been known that there is an association between food and pain, as people with chronic pain often struggle with their weight. Researchers at the Del Monte Institute for Neuroscience may have found an explanation in a new study that suggests that circuitry in the brain responsible for motivation and pleasure is impacted when someone experiences pain. “These findings may reveal new physiological mechanisms linking chronic pain to a change in someone’s eating behavior,” said Paul Geha, M.D., lead author on the study published in PLOS ONE. “And this change can lead to the development of obesity.”

Finding pleasure in food comes from how our brain responds to what we are eating. In this study researchers were looking at the brain’s response to sugar and fat. Using a gelatin dessert and pudding researchers altered the sugar, fat, and texture of the foods. They found that none of the patients experienced eating behavior changes with sugar, but they did with fat. Those with acute lower back pain who later recovered were most likely to lose pleasure in eating the pudding and show disrupted satiety signals – the communication from the digestive system to the brain – while those with acute lower back pain whose pain persisted at one year did not initially have the same change in their eating behavior. But chronic lower back pain patients did report that eventually foods high in fat and carbohydrates, like ice cream and cookies, became problematic for them over time and brain scans showed disrupted satiety signals.

“It is important to note, this change in food liking did not change their caloric intake,” said Geha, who first authored a previous study published in PAIN that recent research is building on. “These findings suggest obesity in patients with chronic pain may not be caused by lack of movement but maybe they change how they eat.”

Brain scans of the study participants revealed that the nucleus accumbens – a small area of the brain mostly known for its role in decision-making – may offer clues to who is at risk to experience a long-term change in eating behavior. Researchers found the structure of this area of the brain was normal in of patients who initially experienced changes in their eating behavior but whose pain did not become chronic. However, patients whose eating behavior was normal, but whose pain became chronic had smaller nucleus accumbens. Interestingly, the nucleus accumbens predicted pleasure ratings only in chronic back pain patients and in patients who became chronic after an acute bout of back pain suggesting that this region becomes critical in motivated behavior of chronic pain patients. Previous research by Geha, found a smaller nucleus accumbens can indicate if someone is at a greater risk of developing chronic pain.

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Mid Back Stretches & Exercises for Pain Relief

Back Pain | Ask Doctor Jo


Mid back pain can make it difficult to perform everyday activities. Here are some of my favorite mid back stretches and exercises to help relieve the pain. Rhomboid stretch, thoracic side bend, and thoracic rotation are all simple stretches to get started. These should help loosen up tight mid back muscles and relieve pain in the mid back area. Seated Ts, seated rows, and bear hugs are all simple exercises to help strengthen the muscles. These should help loosen up tight mid back muscles and relieve pain in the mid back area as well.

Posted on Pain Management

Later hit: Does cannabis ease pain, speed recovery in injured athletes?

Revolutionary mmj patch successfully treats fibromyalgia and diabetics nerve pain

Increasingly, professional athletes in sports ranging from football to bicycling to long-distance running have turned to using cannabis to reduce pain from post-game injuries and to help speed recovery.

Anecdotal reports of cannabis’ purported benefits abound, but empirical evidence is scant. Today, the National Football League announced funding of a novel clinical trial that will assess the therapeutic efficacy (and any possible adverse effects) of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis; cannabidiol (CBD), the second most prevalent active ingredient in cannabis but not psychoactive; and a combination of the two for treating post-competition pain caused by soft tissue injury, compared to a placebo.

Co-led by Mark Wallace, MD, a pain management specialist and director of the Center for Pain Medicine at UC San Diego Health, and Thomas Marcotte, PhD, professor of psychiatry at University of California School of Medicine and co-director of the Center for Medicinal Cannabis Research (CMCR) at UC San Diego, the randomized, double-blind trial will involve testing and monitoring of professional rugby players.

Professional rugby was chosen for the first trial because it approximates the types of injuries also experienced by NFL players, the researchers said, and was logistically more feasible.

“An innovation of this research is using a ‘real-world model’ of the NFL’s competitive injury burden with a group of elite athletes who experience similar injuries,” said Marcotte. “It’s a first-of-its-kind randomized trial to examine the possible practical efficacy of cannabinoids on post-competition pain.”

The primary goal of the trial will be to evaluate pain relief and recovery. Secondary goals include assessment of any effects on physical function, sleep, cognition and mood.

Participating athletes who report post-game pain that meets a specific threshold will have a blood sample drawn and be assigned to vaporize either 4 percent THC, 12 percent CBD, a combination of THC and CBD at those percentages or a placebo for up to four times per day over the following 48 hours. They will be asked to self-report pain scores via a cell phone application at regular intervals during those 48 hours. A second blood draw will be taken the day after each game.

Practicing, competing and living with pain are unavoidable elements of a professional athlete’s life. As a result, efforts to ameliorate the negative effects of pain are long-standing, and include the use of prescription pain medications, including opioids.

Cannabis has been used for medical purposes for centuries around the world. Increasingly, there are efforts to develop and promote it as a safer pharmacological alternative to other forms of pain relief and there is some scientific research suggesting that THC is effective in relieving certain types of pain.

Wallace, a professor of anesthesiology and chief of the Division of Pain Medicine at UC San Diego School of Medicine, has integrated the use of medical cannabis into clinical practice.

“Much of the knowledge we used for dosing medical cannabis in our pain clinic came from the studies supported by CMCR, which showed there is a therapeutic window of analgesia with low doses of THC reducing pain and high doses worsening pain.

“We will build on the CMCR research and our clinical experience to translate efficacy and safety for sports injury recovery.”

The trial will be conducted following regulatory reviews by the Food and Drug Administration, the Drug Enforcement Administration, the UC San Diego Institutional Review Board and the Research Advisory Panel of California.

Though no conclusions can be drawn until the study is completed and data analyzed, investigators hypothesize that THC and THC/CBD combinations will prove superior to CBD and placebo for pain reduction; and CBD alone will prove superior to placebo.

Posted on Pain Management

Scientists reveal mechanism for colon pain and inflammation

PAR2 in normal and inflamed tissue


In normal tissue, PAR2—seen here in fluorescent green—is found on the surface of cells, but in inflamed tissue, it moves from the surface of cells to compartments within cells called endosomes. CREDIT Bunnett Lab, NYU Dentistry

Researchers at the NYU Pain Research Center have identified a mechanism that underlies inflammation and pain in the colon, and demonstrated that blocking a key receptor from entering colon cells can inhibit inflammation and pain, uncovering a potential target for treating pain in inflammatory bowel disease. 

Their study, published in the Proceedings of the National Academy of Sciences (PNAS), was conducted in mice with colitis, an inflammatory disease marked by chronic and sometimes painful inflammation of the large intestine.

The digestive tract is home to a large number of proteases, or enzymes that break down proteins. These proteases come from a variety of sources, including the microbiota, inflammatory cells, or digestive enzymes in the intestine.

While proteases are important for digestion and help to degrade proteins in the gut, many also signal cells by activating specific G protein-coupled receptors (GCPRs). GCPRs are a large family of receptors that regulate many processes in the body and are the target of one third of clinically used drugs. When proteases activate one such GCPR—protease-activated receptor-2, or PAR2—on nerve cells, it causes the release of mediators that produce pain.

Studies show that protease activation of PAR2 is involved in gastrointestinal diseases that can be associated with pain, including inflammatory bowel disease, irritable bowel syndrome, and cancer. But until now, scientists have not fully understood the receptor’s signaling mechanism and how it induces pain.

To pinpoint PAR2’s location in the gut, the researchers created a mouse model in which the gene for PAR2 is fused to a green fluorescent protein. When a cell expresses PAR2, it lights up green, allowing the researchers to precisely see where the receptor is positioned. They found that PAR2 was very highly expressed on the surface or membrane of the epithelial cells that line the small and large intestines, and to a lesser extent in nerve fibers in these areas.

The researchers then discovered a key difference in the location and behavior of PAR2 in healthy mice versus mice with colitis. In healthy mice, PAR2 was found on the membrane of colonic epithelial cells, but in mice with colitis, it shifted from the surface of cells to compartments within cells called endosomes. When the receptor moved into endosomes, it generated signals that cause inflammation and pain by disrupting the normal protective function of cells lining the colon. 

“We identified not only where this receptor is in the digestive tract, but also how it signals inflammation and pain in the colon,” said Nigel Bunnett, PhD, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and the study’s senior author. “This more complete understanding of PAR2 and its signaling mechanism could ultimately help us to better treat inflammatory and painful diseases of the colon.”

Additional studies using human colon tissue confirmed that activating PAR2 induces inflammation in the colon.

If PAR2 moving from the surface of cells into endosomes leads to inflammation and pain, could blocking the receptor from entering cells limit inflammation and pain? To test this idea, the researchers prevented the movement of PAR2 into cells by knocking down the expression of a protein called dynamin-2. Keeping the receptor out of cells did, in fact, inhibit signaling and significantly reduced pain and inflammation.

The findings suggest that PAR2—and specifically, PAR2 in endosomes—may be a useful target in treating pain in inflammatory bowel disease.

“This could be achieved through blocking PAR2 from entering cells, as we did in this study by inhibiting dynamin-2,” said Bunnett. “It could also mean getting drugs that activate PAR2 not just to the surface of cells, but into the interior of cells using nanoparticles to reach the receptorin endosomes.”