Nausea is a bit of a catchall term describing that unpleasant, sick feeling that can hit us as a result of anything from pregnancy or migraine, to eating spoiled food or undergoing chemotherapy. But scientists still don’t understand precisely how nausea works on a mechanistic level. Studies led by cell biologists at Harvard Medical have now generated new insights that improve our understanding of the brain pathways that control nausea.
The team’s research, headed by Stephen Liberles, PhD, professor of cell biology in the Blavatnik Institute at HMS, uncovered a mechanism, in mice, by which inhibitory neurons in a specific brain region known as the area postrema suppress the activity of nausea-causing excitatory neurons to tamp down nausea.
The findings illuminate the basic biology of nausea, and if affirmed in further studies in animals and humans, could inform the development of better anti-nausea medications.
Liberles and colleagues reported their findings in Cell Reports, in a paper titled, “A brainstem circuit for nausea suppression,” in which they concluded, “These findings provide insights into the basic organization of nausea-associated brainstem circuits and reveal that area postrema inhibitory neurons are an effective pharmacological target for nausea intervention.”
Nausea evolved to help us survive by prompting vomiting when we ingest toxins or contract an infection. However, nausea can become a major problem when it occurs in other contexts—for example, during pregnancy or as a side effect of treatments for cancer or diabetes. In fact, “nausea is one of the most encountered symptoms in healthcare,” the authors wrote. If untreated, uncontrolled vomiting can lead to electrolyte imbalances and, in rare cases, life-threatening dehydration.
Current medications for nausea associated with these conditions aren’t all that effective, largely because scientists don’t have a detailed understanding of how the brain produces the sensation. As the authors further pointed out, “New strategies for nausea intervention are needed and may be enabled by a mechanistic understanding of how the sensation of nausea arises.” Lead author Chuchu Zhang, PhD, a research fellow in cell biology at HMS, pointed out, “We cannot really develop better treatment strategies until we know the mechanism of nausea.”
Zhang and Liberles are studying a region of the brain stem called the area postrema, which appears to be involved in nausea. “Classical studies involving brain lesion and stimulation revealed a tiny brainstem structure termed the area postrema that mediates nausea responses to several visceral threats,” the scientists stated. Earlier research found that stimulating this brain region induces vomiting, while disabling it reduces nausea, “… but how it plays a role in nausea was not known, so we thought this would be a good place to start,” Zhang said.
In a 2020 study in Neuron, Zhang and Liberles identified excitatory neurons in the area postrema that cause nausea, along with their associated receptors. Specifically, they characterized neurons that express the receptor for GLP1, a protein linked to blood sugar and appetite control. This receptor, they noted, is a common target for diabetes drugs, for which nausea is a major side effect. When neurons with GLP1 receptors were turned on, mice showed signs of nausea, and when the neurons were turned off, the nausea behaviors stopped.
The team also mapped these nausea-inducing neurons, located outside the blood-brain barrier, which allows them to easily detect toxins in the blood. “Understanding what receptors are expressed in the area postrema tells us what kinds of pathways may be involved in nausea signaling,” Zhang said. “One traditional approach to intervene in nausea is to block those signaling pathways using pharmacological inhibitors,” Liberles added.
However, the researchers wondered if there could be a different way to reduce nausea, which instead focuses instead on inhibitory neurons that suppress the excitatory neurons in the area postrema. So, for their newly reported study, the investigators explored the structure and function of inhibitory neurons in the area postrema. “The functions of area postrema inhibitory neurons are unclear,” the team noted in the paper. However, based on their previous research, “we hypothesized that at least some inhibitory neuron types may suppress the activity and function of area postrema excitatory neurons, including those involved in nausea.”
Mapping these inhibitory neurons revealed that they form a dense network that connects with nearby excitatory neurons. When the researchers activated the inhibitory neurons, the mice stopped nausea behaviors that are typically caused by excitatory neurons.
Through further studies, the team then identified three types of inhibitory neurons in the area postrema. One of these types expresses a receptor for GIP, a small protein released by the digestive system after eating, stimulating the release of insulin to control blood sugar. “We focused on one subpopulation of area postrema inhibitory neurons that express the receptor (GIPR) for glucose insulinotropic peptide (GIP),” the team stated. “GIP is a gut-derived hormone and incretin released upon nutrient intake that rapidly promotes insulin release … Small molecules that activate the receptor for another incretin, GLP1, are clinical mainstays for diabetes treatment but induce nausea as an adverse side effect through area postrema excitatory neurons.”
Zhang said, “We were curious whether this population of inhibitory neurons marked by the receptor for GIP could be manipulated to suppress nausea behavior, and how that mechanism works.” When the researchers used GIP to activate these inhibitory neurons, inhibitory currents prompted by the chemical messenger GABA flowed to nearby excitatory neurons, reducing their activity. As the team explained, “The gut hormone glucose insulinotropic peptide … activates area postrema inhibitory neurons that project locally and elicit inhibitory currents in nausea-promoting excitatory neurons through γ-aminobutyric acid (GABA) receptors.”
On a behavioral level, giving mice GIP to activate these inhibitory neurons eliminated nausea behaviors. On the flip side, when the inhibitory neurons were destroyed, mice continued to show signs of nausea, even after receiving GIP. The team commented, “GIP blocks behavioral responses to poisons in wild-type mice, with protection eliminated by targeted area postrema neuron ablation.”
Because mice don’t vomit, Zhang noted, the study relied on observing the presence of behaviors suggestive of nausea, such as avoiding toxic substances. Given that the same brain pathways exist in humans, the researchers say the mechanism is likely conserved. “By identifying inhibitory neurons that suppress nausea in a pharmacologically accessible brain region, we can simply engage these neurons to counteract nausea responses,” Liberles explained.
The authors concluded, “Together, experiments here reveal that GIP suppresses poison responses through a dedicated neuronal pathway, key insights into area postrema circuit organization, and a potential strategy for nausea intervention that involves targeting of brainstem inhibitory neurons.”
Zhang continued, “The brain stem inhibitory neurons in the area postrema are potentially a great clinical target for anti-nausea drug development. It’s definitely a new strategy for developing anti-nausea treatments.”
GIP is already being studied as a potential treatment for nausea, Zhang said. In fact, preliminary research has shown that giving GIP or activating GIP receptors can reduce nausea in animals that do vomit, including ferrets, dogs, and shrews. Scientists are currently working on incorporating GIP into diabetes treatments that target GLP1 receptors, with the goal of decreasing nausea as a side effect.
Zhang and Liberles plan to continue exploring the basic biology of nausea, including how these inhibitory neurons in the brain are naturally activated, and what other brain regions are involved in controlling their activity. The team also wants to investigate additional receptors expressed by inhibitory neurons, and the various signaling factors that engage them.
“Because there are different ways to trigger nausea, there are probably different receptors and signaling factors involved that could be used as drug targets to suppress nausea.” Zhang pointed out. “We want to know more about the various nausea mechanisms so that we can develop even better treatment strategies that are tailored to specific conditions.”