Behind the pain

Scientists discuss recent advances and the challenges of molecular mechanisms related to pain and analgesia.

By  Fábio de Castro

Agência FAPESP – Brazilian and foreign researchers met on July 14 at the Butantan Institute in São Paulo to discuss the most recent advances and the main challenges of research on molecular and cellular mechanisms linked to pain and analgesia.

The workshop was sponsored by the Center for Applied Toxinology (CAT), one of FAPESP’s Research, Innovation and Dissemination Centers (RIDC). The event was coordinated by Yara Cury, researcher at the Butantan Institute, and Sergio Henrique Ferreira, of the Ribeirão Preto Medical School at Universidade de São Paulo (USP).

According to Hugo Aguirre Armelin, CAT director, during the event the students and researchers that packed the auditorium of the Butantan Institute’s Biological Museum could see firsthand that Brazil is producing high level science in the area of pain and analgesia.

“One of the objectives of the workshop was highlighting the quality of the work that has been carried out at CAT, in comparison to the research presented by some of the main foreign scientists in the area. It was an opportunity to evaluate the level of our research and show students that they also have the opportunity to do what is being done abroad here in Brazil,” he told Agência FAPESP.

According to Armelin, the Butantan Institute’s Pain and Signaling Laboratory, headed by Cury, is one of the most developed under the auspices of CAT.

The laboratory team discovered crotalphine, a toxin  taken from the venom of the South American rattlesnake (Crotalus durissus terrificus) with potent analgesic activity. The institution has held the patent for the toxin since 2004 and joined forces with the pharmaceutical industry to develop a medicine.

“This discovery was only possible because for years, Professor Yara Cury has worked with a solid team of researchers studying the mechanisms of pain and analgesia. Without this scientific basis, pursuing interesting toxins would be useless. We need to carefully study the mechanisms involved in pain and analgesic activity,” he said.

The series of workshops organized by CAT also aims to show  what the center has managed to develop over the last decade. As RIDCs typically last 11 years, CAT’s project will end in 2011.

“This does not mean that the laboratory will end its activities. On the contrary, the lab will be part of the Butantan’s inheritance from RIDC-FAPESP. Like other CAT groups, the project was consolidated over the 11-year period and is now walking on its own two feet with enough ‘muscle’ to move forward competitively. During the period, we also trained young leaders, forming new groups that are now well-established,” affirmed Armelin.

Basic and applied research  
 
According to Cury, the excellent work developed at CAT owes in part to the fact that the Butantan Institute offers the structure to work not only with molecular biology techniques, but also with in vivo research. For this reason, the workshop included topics of discussion on current research in animal models.

“In vitro studies offer a very precise view of the molecular mechanisms and what occurs with the substance that causes pain or analgesia. But when this is transferred to in vivo studies, the scenario changes completely, because [in this environment] the mechanism is associated with the entire biological system. And  one must address all these aspects. Our objective is to work in parallel with these two aspects and the workshop discussed both perspectives,” said Cury.

According to the scientist, without animal models, it would be impossible to turn knowledge on the mechanisms of pain and analgesia into drugs capable of controlling pain in humans or to understand why one feels pain with specific diseases.

“Use of animal models cannot be left out of discussions on the most current developments in cellular and molecular mechanisms of pain and analgesia,” she said.

The experience of discovering crotalphine, according to Cury, clearly revealed the importance of simultaneously developing applied and basic studies. 

“We managed to isolate the substance and verify its analgesic activity. But we need to understand how the substance works and we still don’t know its molecular target. Understanding that, we can uncover the signaling involved and develop other substances that are more or less effective than crotalphine,” she explains. 

The substance can be used as a model to develop new substances, according to Cury. “It may not even become a medication, but based on the increased knowledge that these studies have contributed to basic research, it will be possible to improve other substances that we are developing to become analgesics. At CAT, we are lucky to be able to work with the two aspects,” she explained.

According to the Butantan researcher, one of the main difficulties in the research area is that when a drug is developed for a specific pain, it acts on a specific spot in a molecular mechanism, whose significance may not be limited to pain, but could impact other physiological systems.

“In these cases, the medicine interferes with pain, but also alters the entire system, causing adverse affects. For this reason, a better understanding of the molecular mechanism is necessary in order to develop a drug that is more precisely suited to the receptor that is altered by the diseases-related pain. And that is not an easy task. But we have managed many advances with new approaches and techniques,” highlights Cury.

During the workshop, Daniel Tracy from Duke University discussed “Alternatives to mammalian pain models: using Drosophila to identify novel nociceptive genes.” Carlos Parada from Universidade Estadual de Campinas (Unicamp) spoke about “Oligonucleotide antisense as a new pharmacological tool to control pain.”

Giles Rae of the Universidade Federal de Santa Catarina (UFSC), presented a workshop on  “Endothelins as potential new targets for pain relief: what is the current picture?”.
 
Lakshmi Devi, Mount Sinai School of Medicine, debated “Interactions between cannabinoid and opioid receptors during neuropathic pain.”

“Peripheral injury regulates opioid receptor expression and increases the antinociceptive effect of crotalphine, an opioid-like drug” was the topic chosen by Yara Cury. Jeffrey Mogil,  McGill University (Canada), presented a workshop on “What’s wrong with animal models of pain?.”