Endothelin receptor may play role in sickle cell pain

MONTREAL, CN (September 10, 2009) − Agonizing physical pain, known as vaso-occlusive pain, can afflict children who have sickle cell disease (SCD). In some cases infants as young as two months of age suffer vaso-occlusive pain so severe that opiate medications and hospitalizations are their only relief. Researchers believe vaso-occlusion is caused by a blockage of the blood vessels that occurs when sickle shaped red cells attempt to pass through the round blood vessels. How vaso-occulsion leads to pain, and its impact on males and females are still unknown. A University of South Carolina research team suggests that a naturally occurring chemical in the body, endothelin (ET), may play a role. ET is produced by most tissues in the body and is highly concentrated in blood vessels. It causes blood vessels to contract, which contributes to pain. ET is the most potent blood vessel constrictor currently known. Characterized by a molecular structure similar to snake venom, ET can pack the punch of a bee sting.

Researchers Sarah Sweitzer, Federico Perez and Alvin McKelvy, Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, Columbia have conducted several studies involving ET and vaso-occlusion pain. They are presenting an update of their work, "Sexually Dimorphic Nociceptive Priming by Endothelin: Involvement of the Endothelin B Receptor," as part of the 11th International Conference on Endothelin being held September 9-12, 2009 in Montreal, CN. The program is being sponsored by the American Physiological Society (APS; www.the-aps.org). A copy of the complete program is available at http://the-aps.org/meetings/aps/ET11Montreal/index.htm.

Pain Early and Later in Life: Two-Part Study

The study was conducted in two parts. During phase I, 50 SCD+ adolescents (male and females between ages 8-18) were studied at the university's Children's Cancer and Blood Disorder Center. During the youngsters' routine visits researchers videotaped the participants during the needle stick blood draw process and asked the participants to rate their pain level during the blood draw. The scoring system used emoticons that indicated pain levels between 0-10. The blood was then analyzed for the presence of endothelin, which was found to increase with the child's increasing pain

In phase II the team constructed an animal model using endothelin that allowed them to control the age at first vaso-occlusive pain and the effect of repeated vaso-occlusive events on subsequent pain events.

Endothelin was administered to young rats seven days after birth and again on day 11 to model repeated painful vaso-occlusive type episodes. A different group experienced its first ET-1 exposure 11 days after birth. The two groups were compared.

Males More Sensitized to Pain

In the animal model the researchers found:

• Males had a greater pain response if they had been "primed" to pain by a first exposure to ET-1. Moreover, their pain radiated virtually throughout the body rather than being confined to the localized area of the pain experience.
• By contrast, females had a lower pain response if they had been primed, meaning they were de-sensitized to pain after a first exposure to ET-1. Further, unlike the males, female desensitization was localized rather than widespread.

The data from the clinic study showed similar results:

• Male SCD patients in the clinic study were sensitized to pain after "priming" whereas female SCD patients were de-sensitized.

Role of Endothelin, Endorphins and Hormones

According to Sweitzer, these findings may be due to a change in the endothelin B receptor (ETBR). This receptor is important in the body's internal ability to control pain. That is because ETBR resides in many places within the body, including the cells that make up skin.

When the receptor is activated, it releases endorphins (the body's natural opiate) throughout the body. "We are finding that the males who experience repeated pain do not have as much of the receptor and therefore do not release as much of the endorphins," Sweitzer explained.

Conversely, the team has found that females have more of the ETB receptor. "Females experience better pain control and have more of the receptor. This juxtaposition may help explain sensitivity by gender. The difference in the endothelin receptor may help explain why we are finding males more sensitized to pain."

Source: American Physiological Society