In search of a more effective pain reliever with fewer side effects, a team of 18 Brazilian researchers and one North American decided to study people with a genetic disease that affects only one in every 125 million people in the world, called Cipa (Congenital Insensitivity). to Pain with Anhidrosis). Since they do not feel pain or heat, people with this condition cannot react promptly to situations that can cause harm, such as illness or burns. In addition, they do not sweat, suffering excessive increases in temperature. By understanding what prevents these people from experiencing painful stimuli, the researchers identified a new analgesia strategy and created an experimental compound capable of reducing pain. If it goes ahead, the study could help treat chronic pain, which affects about a third of the world’s population and can lead to inability to work, depression and anxiety disorder, according to the SBED (Brazilian Society for the Study of Pain) .
“We believed that, by better understanding the mechanism of a disease that blocks pain, we could find useful signaling pathways in the formulation of new analgesics”, explains biochemist Deborah Schechtman, from IQ-USP (Institute of Chemistry at the University of São Paulo) and coordinator of the study, which was featured on the cover of the April 26 issue of the journal Science Signaling.
The initial step was to better understand why a protein called a TrkA (TRopomyosin Kinase A) does not work in patients with Cipa, blocking the nerve pain signal. After elucidating the flaws in this mechanism, the researchers formulated and developed a molecule capable of overcoming the problem. “We created an analgesic that significantly reduced pain in tests carried out on mice”, celebrates Schechtman.
This new analgesic acts on so-called nociceptors, common neurons in tissues or organs exposed to stimuli that can cause pain, such as skin, muscles, stomach and intestines. When triggered, the neuron stimulates the production of a substance called NGF (Neural Growth Factor), which binds to the TrkA receptor. Then the neuron fires the electrical impulse that travels along a nerve to the regions of the brain that interpret pain and contribute to making the person react before they are even aware, moving away from what causes the pain (a burn, for example). .
“The advantage of this approach is to target specific mechanisms that cause pain in different conditions”, explains pharmacologist Thiago Mattar Cunha, from FMRP (USP Ribeirão Preto School of Medicine), who was not involved in the work. A few decades ago, scientists and companies thought there was a single pain mechanism, which opioids, traditional pain relievers, or anti-inflammatories would treat through different strategies. Today, it is known that pain caused by diabetes, chronic inflammation or cancer, for example, works in different ways and is not always stopped by the medicines at hand.
Chronic pain is treated with several drugs that block impulse transmission in the neuron. “Acetylsalicylic acid, better known as Aspirin, acts at the site of inflammation, but not on other pain mechanisms, while opioids have a general effect, acting on the central nervous system, but with side effects such as sleep and addiction. In the case of dipyrone, the active principle of Novalgina, the mechanism of action is not well known”, points out Cunha, emphasizing the need for more specific analgesics.
Blocking the region of TrkA where NGF binds would therefore be the theoretically most effective option for eliminating pain. The problem is that, as the name suggests, NGF has another important function: stimulating the growth of neurons and the regeneration of nervous tissue after some injuries. Therefore, the few drugs that block the action of NGF have many side effects. If it doesn’t work, there is no pain, but brain development problems and cognitive disorders can occur.
“We needed an alternative, a signaling pathway that would block the impulse of pain, but not the growth of neurons”, explains biologist Camila Squarzoni Dale, from the Institute of Biomedical Sciences at USP, who also participated in the work. The answer to this dilemma lay in people with Cipa.
The USP team listed the mutations associated with the disease, identified in 230 people in the last 50 years in studies carried out around the world. Four of them had mutations that blocked only one signaling pathway mediated by NGF, that of the enzyme phospholipase C, and one of the patients who had milder symptoms felt some pain. “This suggested that they had a mutation that only affected the pain signaling pathway, indicating new ways to control pain,” comments Schechtman.
To discover the effect of the mutation presented by each patient on the functioning of TrkA, the researchers created three-dimensional models of these receptors on computers at the CNPEM (National Center for Research in Energy and Materials), in Campinas, and performed virtual tests to see how they interacted. with other molecules inside and outside the neurons that perceive pain. A previous study indicated that one of the molecules activated by TrkA is phospholipase C, but the researchers did not know what its role was in different types of pain. Furthermore, this protein does not appear to affect neuron growth and regeneration.
Based on these observations, the group developed and synthesized a molecule, named TAT-pQYP, which binds to TrkA in place of phospholipase C, preventing its action and reducing pain. In the experiments, mice received an injection in their hind legs that caused inflammation and pain. Then, a device measured the intensity of the animals’ mechanical reaction to touch, which was 40% higher after the application of TAT-pQY. The possible side effects of the substance have not yet been studied.
“It’s an elegant, complete and well-done piece of work, which studies the molecular mechanism that causes Cipa, computer modeling and the development of a molecule”, says Cunha. But he warns: “Between the experimental substance and the commercialized drug there is a long way, which does not always work”. Two issues make it difficult for TAT-pQYP to become a drug to treat pain. The molecule is very complex, which makes its production difficult by the pharmaceutical industry, in addition to being large.
Now the group plans to identify what kind of pain can be treated by blocking this pathway. The objective is to develop the basis for a medication for chronic pain with fewer side effects than opioids, which, by generating dependence, have become a public health problem in the United States. In this first stage, the team had the support of Fapesp (Fundação de Amparo à Pesquisa do Estado de São Paulo), Capes (Coordination for the Improvement of Higher Education Personnel) and CNPq (National Council for Scientific and Technological Development). Pharmaceutical companies are interested in the issue, it is about disputing a market that moves around R$ 2.6 billion in the country.
In his April column in Science on drug development, Novartis chemist Derek Lowe, warned about the difficulty of developing new analgesics. He commented on previous work by Schechtman’s group, at a more advanced stage of development, with a neuron protein called Nav 1.7, which is important in the generation and transmission of the nerve signal, especially in pain neurons. According to him, it was possible to elaborate compounds to block Nav 1.7, but “none of them showed significant effectiveness”. As Lowe wrote, the development of analgesics is a rock that has already sunk many ships, although it brings new knowledge about the origin of a fundamental mechanism.