Molecular Pathway Transmits Itches, but Not Ouches

Along the signaling pathways connecting the skin and the brain, there are gatekeepers, neurotransmitters that relay signals, or not, depending on whether the signals are of the sort the brain interprets as itching sensations, or pain sensations. These gatekeepers, found recently by scientists based at North Carolina University, raise the possibility that drugs could be developed targeting itching, but not pain, or vice versa.

A particular kind of neurotransmitter, brain natriuretic peptide (BNP), has been studied by North Carolina State University researchers. BNP is expressed in a small number of sensory nerve cells or neurons. The researchers knew that BNP helps transmit itching sensations from the skin to the brain. But was it also involved in transmitting pain sensations?

To explore this question, the researchers looked at whether BNP played a role in transmitting acute, inflammatory, or neuropathic pain in mice. They found that BNP plays no role in pain transmission.

The results were the same for regular mice and those that lacked the BNP gene. “That means BNP was not involved for any of these distinct types of pain,” said Santosh Mishra, Ph.D., assistant professor of neuroscience in NC State's College of Veterinary Medicine. “We know that if we target BNP, we won't be inhibiting pain; we'll be inhibiting itch.”

Details of the researchers’ work appeared October 2 in the journal Molecular Pain, in an article entitled “Brain Natriuretic Peptide (BNP) Expressing Sensory Neurons Are Not Involved in Acute, Inflammatory or Neuropathic Pain.” The article describes how researchers led by Mishra compared behavioral responses of BNP-knockout (KO) mice with their wild-type littermates.

“First, we showed that BNP is not required in chemically-induced pain responses evoked by the administration of capsaicin, allyl isothiocyanate (AITC), adenosine 5′-triphosphate (ATP), or inflammatory soup,” wrote the article’s authors. “We further measured pain behaviors and found no involvement of BNP in hot, cold, or mechanical nociceptive responses in mice, nor did we find evidence for the involvement of BNP in neuroinflammatory sensitization elicited by complete Freund’s adjuvant (CFA) or in neuropathic pain.”

The authors asserted that their findings are consistent with the hypothesis that BNP does not play a functional role in mediating pain. The authors also suggested that more study needs to be done to elucidate the spinal complexity for pain and itch sensation.

“For us, it's very important to understand the neural circuits or pathways so that we can develop therapies specifically for pain or itch, instead of targeting it as a whole system,” added Mishra, the article’s corresponding author. “This work shines a light on these different pathways for pain and itch.”

Pain or itching sensations begin when a nerve cell on the surface of the body reacts to a stimulus, starting a chain reaction that moves from cell to cell.

“Neurons react to a stimulus by depolarizing, which is how the cells talk to each other,” Mishra explained. “Once it's depolarized, a neuron releases a neurotransmitter, which starts the communication from one cell to another, moving from the periphery of the body to the central nervous system.”

The neural pathway takes the message to the spinal cord, which is connected to the brain. The brain interprets the signals from the nerves, creating the sensations of pain and itching.

“If we know how these sensations are transmitted, we can design specific drugs or therapies to block the neurotransmitters, block the receptors for the neurotransmitters, or reduce the degree to which those neurotransmitters work,” Mishra speculated. “I call these the gatekeepers because they are sitting in between the skin and the central nervous system.”

The goal is to develop treatments that interrupt the pain or itch signals closer to the source.

“If we can block the sensation at the peripheral level, in the skin, that is a much friendlier way than to try to target the sensation once it reaches the brain,” Mishra insisted. “We know the importance of pain management. Studying itching sensations is a relatively new field, but if we look at the number of diseases where itch is a major symptom, it includes not only atopic dermatitis but also nervous system disorders such as multiple sclerosis, as well as infection and end-stage kidney disease. This work is an initial step in gaining a better understanding.”