Medical discovery first step on path to new painkillers

A major medical discovery by scientists at The University of Nottingham could lead to the development of an entirely new type of painkiller.

A drug resulting from the research, published in the journal Neurobiology of Disease, would offer new hope to sufferers of chronic pain conditions such as traumatic nerve injury, for which few effective painkillers are currently available.

The work, led by Dr Lucy Donaldson in the University’s School of Life Sciences, in collaboration with David Bates, Professor of Oncology in the University’sCancer Biology Unit, focuses on a signal protein called vascular endothelial growth factor (VEGF).

VEGF controls the re-growth of blood vessels in tissues which have been damaged by injury. It is a widely targeted compound for cancer, eye disease and other illnesses in which abnormal blood vessel growth occurs.

Drugs are used to inhibit the VEGF in cancer, which can otherwise lead to the formation of new blood vessels that provide oxygen and nutrients to tumours.

Professor Bates and colleagues had previously discovered in 2002 that VEGF comes in two forms and acts like a switch — one which turns on the growth of blood vessels and another that blocks growth.

Pain prevention

However, this latest research has shown for the first time that these two forms of VEGF not only act on blood vessels but also differently affect the sensory nerves that control pain.

The academics discovered that the VEGF that promotes blood vessel growth causes pain, while the other, which inhibits blood vessel growth, prevents pain.

The study has centred on understanding how these two types of VEGF work and why the body makes one form rather than the other.

The academics have been able to switch from the pain stimulating form to the pain inhibiting VEGF in animal models in the laboratory and are now investigating compounds to replicate this in humans. It is thought these compounds could form the basis for new drugs to be tested in humans in clinical trials.

Electric stimulation of brain releases powerful, opiate-like painkiller

Researchers used electricity on certain regions in the brain of a patient with chronic, severe facial pain to release an opiate-like substance that’s considered one of the body’s most powerful painkillers.

The findings expand on previous work done at the University of Michigan, Harvard University and the City University of New York where researchers delivered electricity through sensors on the skulls of chronic migraine patients, and found a decrease in the intensity and pain of their headache attacks. However, the researchers then couldn’t completely explain how or why.

The current findings help explain what happens in the brain that decreases pain during the brief sessions of electricity, says Alexandre DaSilva, the senior researcher in the study from the University of Michigan School of Dentistry. Other study authors include DaSilva’s PhD student, Marcos DosSantos, and also Dr. Jon-Kar Zubieta from the Molecular and Behavioral Neuroscience Institute.

In their current study, DaSilva and colleagues intravenously administered a radiotracer that reached important brain areas in a patient with trigeminal neuropathic pain (TNP), a type of chronic, severe facial pain. They applied the electrodes and electrically stimulated the skull right above the motor cortex of the patient for 20 minutes during a PET scan (positron emission tomography). The stimulation is called transcranial direct current stimulation (tDCS).

The radiotracer was specifically designed to measure, indirectly, the local brain release of mu-opioid, a natural substance that alters pain perception. In order for opiate to function, it needs to bind to the mu-opioid receptor (the study assessed levels of this receptor).

"This is arguably the main resource in the brain to reduce pain," DaSilva said. "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. (Therefore), we can increase the power of this pain-killing effect and even decrease the use of opiates in general, and consequently avoid their side effects, including addiction."

Most pharmaceutical opiates, especially morphine, target the mu-opioid receptors in the brain, DaSilva says.

The dose of electricity is very small, he says. Consider that electroconvulsive therapy (ECT), which is used to treat depression and other psychiatric conditions, uses amperage in the brain ranging from 200 to 1600 milliamperes (mA). The tDCS protocol used in DaSilva’s study delivered 2 mA, considerably lower than ECT.

Just one session immediately improved the patient’s threshold for cold pain by 36 percent, but not the patient’s clinical, TNP/facial pain. This suggests that repetitive electrical stimulation over several sessions are required to have a lasting effect on clinical pain as shown in their previous migraine study, DaSilva says.

The manuscript appears in the journal Frontiers in Psychiatry. The group just completed another study with more subjects, and the initial results seem to confirm the findings above, but further analysis is necessary.

Next, researchers will investigate long-term effects of electric stimulation on the brain and find specific targets in the brain that may be more effective depending on the pain condition and patients’ status. For example, the frontal areas may be more helpful for chronic pain patients with depression symptoms.