GPCRs and pain

Published on March 28, 2019   36 min

Other Talks in the Therapeutic Area: Neurology

Hi. This is Christoph Stein from Berlin, Germany and I was asked to talk about G-protein-coupled receptors and pain.
Pain is the processing of sensory information and integrated in the brain. So when you look at this slide all the way on top, this is where the person perceives pain as an integrated response of many different stimuli that start in the periphery and end up in the central nervous system. So now look at peripheral ending of the sensory neuron, all the way at the bottom of this slide, there are many many different stimuli that can initiate this nociceptive process. So at this stage, we talk about nociception which is the beginning of the signal that ends up in the brain. You can see cytokines, you can see proteases, bradykinin, keratinocytes, many different types of physical stimuli, mechanical, heat, cold and chemical stimuli. All of these excite nociceptive neurons at the peripheral ending. Thereafter, there is an action potential that is transmitted by the primary afferent neuron towards the spinal cord where it is transmitted via synaptic processes and then gets transferred upwards to the central nervous system.
In this slide, you see a more detailed view of all the different processes and the receptors, the G-protein-coupled receptors that play a role in this. First of all, you see on A, you see the sensation. That means that in this case, all the different stimuli that I just mentioned but also all the different receptors. Most of them are G-protein-coupled receptors on the primary afferent neuron at the nerve ending. You can see several different examples of G-protein coupled receptors. For example, the 5-HT, the serotonin receptor, the B2R, the so-called the bradykinin receptor, the H1R, the histamine receptor and another important inhibitory receptor, the opioid receptor, all the way to the right. On the lower part of this slide you see all the different stimuli that are actually initiated by the primary afferent neuron. Because the primary afferent neuron also by itself, releases stimulatory substances for example, substance P on the right side or CGRP, calcitonin gene-related peptide on the left side. They also activate different G-protein- coupled receptors on different structures such as blood vessels or mast cells or keratinocytes which then again release stimulatory substances that can initiate nociception. When you look at C on the right side, we see the process that is happening in the spinal cord after the action potential reaches the central ending of this primary afferent neuron. There, you can see that again, different transmitters are released. For example, glutamate, substance P again, CGRP again which themselves then activate G-protein-coupled receptors on the so-called secondary neuron in the spinal cord and transmit this nociceptive signal.