Studying mice, pain researchers at the School of Medicine have identified two key components in the pain cascade that may provide targets for more effective analgesic drugs with potentially fewer side effects.
A team led by Robert W. Gereau IV, Ph.D., associate professor of anesthesiology, reported in the April 6 issue of the journal Neuron the identification of a potassium channel that plays a crucial role in what scientists call pain plasticity, the ability of molecules in the spinal cord to amplify or diminish the response to a painful stimulus.
“The potassium channel we are studying is called ‘Kv4.2’,” said Gereau, who also is chief of the basic research division of the Washington University Pain Center. “Through a series of experiments, we’ve been able to determine that Kv4.2 decreases transmission through the pain pathway. It helps regulate the ability of pain-transmitting neurons to transmit their signals to the brain.”
We sense pain through primary sensory neurons with nerve endings in the skin, the joints, internal organs or muscles. Those nerve cells interpret signals indicating tissue injury or potential injury and transmit these signals to a part of the spinal cord called the dorsal horn. Pain-transmission neurons in the dorsal horn receive those messages and transmit their own pain signals to the brain.
The signals from neurons in the dorsal horn can be either damped down or enhanced, depending upon many factors, according to Gereau. That’s the plasticity that makes some things hurt more than others, even though the painful stimulus itself might not change.
The researchers tested the role of Kv4.2 in damping down the pain response by studying mice that had no Kv4.2 gene, called “knockout” mice. The mice were bred so that some pups in a litter were knockout mice while others were normal, wild-type mice with the gene.
Knockout mice withdrew their paws from a heat source or mechanical stimulus more quickly than their wild-type siblings.
The scientists also looked at dorsal-horn neurons in culture from both wild-type and knockout mice and found that the neurons from the knockout mice fired more readily than neurons from wild-type mice.
“That’s because the inhibitory Kv4.2 channel was gone in the knockout mice,” Gereau said. “It’s hard to say that these mice somehow sense pain more intensely, but their thresholds for withdrawal from heat and touch are much lower than their brothers and sisters that are genetically normal.”
Potassium channels in dorsal horn neurons are regulated by a molecule called “extracellular signal-related kinase” (ERK). Research has demonstrated that if ERK activity is inhibited, much of the spinal cord’s sensitivity to pain can be diminished. But scientists haven’t really known what ERK was doing.
In this study, the research team studied dorsal horn neurons from mice to clarify the relationship between ERK and Kv4.2.
“When an injury occurs, there is a massive barrage of activity in pain-sensing neurons, and as those neurons fire, that causes neurochemical changes in dorsal-horn neurons,” Gereau said. “Those neurochemical changes activate the ERK pathway. One of the things ERK does is modify Kv4.2 so it can’t inhibit the firing of dorsal horn neurons as efficiently as it normally does. Because Kv4.2 can’t do that, more pain signals get sent to the brain.”
Gereau said the experiments demonstrate that Kv4.2 is a primary target for ERK, and he said both molecules are potential targets for drugs to control or eliminate pain.
Many prescribed anti-inflammatory drugs and opioids are known to decrease ERK activity in the spinal cord.
Although they inhibit ERK activity in the spinal cord, Gereau said many drugs have unwanted side effects and potential addiction liabilities.
There have also been problems associated with anti-inflammatory cox-2 inhibitors, such as Vioxx, which was found to increase the risk of serious cardiovascular events, including heart attacks and strokes. Gereau is searching for approaches to pain relief that rely on different mechanisms like ERK and Kv4.2.