Serendipity in science
Neurons are responsible for regulating most bodily functions, including pain and itch, which so far has been our focus of research. However, serendipity partially changed the course of our work during 2015.
A couple of years ago we discovered that glutamate, released from primary afferents, can regulate itch (Lagerström et al, 2010, Neuron) and since then we have been focused on understanding how. Itch is regarded as the most troublesome symptom in several diseases and the intensity of itch often increases during the night with severe consequences for recovery and quality of life. Glutamate interacts both with ionotropic and metabotropic receptors where the latter is involved in modulatory processes. We discovered that the metabotropic receptor mGluR7 is expressed by primary afferent neurons involved in itch regulation and that activation of the receptor restored elevated itch levels back to normal. Furthermore, activation of mGluR7 only regulated itch evoked by histamine and histamine-related compounds. To test our hypothesis that mGluR7 works as a neuronal brake on histamine-sensing primary afferents we injected histamine in the skin of mGluR7 deficient mice and controls where we expected the former to scratch more as the hypothesized brake was missing.
Now, serendipity struck.
Injections of histamine in mGluR7 deficient mice not only resulted in increased itch levels, after 15-20 minutes the mice also started staggering around in their test cage and became almost immobile. We went back to the drawing table and after subsequent analysis of body temperature, plasma and skin samples of the mice, we realized that mGluR7 deficient mice had developed and anaphylactoid shock (Rogoz, Aresh et al, 2016, Cell Reports).
Anaphylaxis is a severe allergic reaction with a life prevalence of 0.05-2.0% (Lieberman et al, 2006, Ann Allergy Asthma Immunol). The condition is characterized by increased itch, dyspnea, drop in body temperature and even unconsciousness and death. The incidence of anaphylaxis is increasing worldwide especially in children under the age of five where it is most often caused by food allergies (Koplin et al, 2011, Curr Opin Allergy Clin Immunol). Allergic events are histamine-dependent and we can now show that the mGluR7 receptor is needed to regulate the activity of nerve cells in the skin, the primary afferents that are activated by histamine. If these nerve cells lack regulation, restricted release of histamine in the skin is enough to evoke a systemic life threatening anaphylactoid reaction (Figure below).