Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity
| Autor: | Marilyn Steyert, Mollie Bernstein, Ida J. Llewellyn-Smith, Julia Kuhn, Katherine A. Hamel, Alexander Etlin, Mahsa Sadeghi, Line S Löken, Madison Jewell, Joao M. Braz, Allan I. Basbaum |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mechanotransduction Mouse Stimulation Neurodegenerative Inbred C57BL Mechanotransduction Cellular Transgenic neuroscience Mice 0302 clinical medicine touch Peripheral Nerve Injuries 2.1 Biological and endogenous factors pain CGRP Aetiology Biology (General) education.field_of_study Behavior Animal General Neuroscience Pain Research General Medicine Posterior Horn Cells mechanical sensitivity medicine.anatomical_structure Hyperalgesia Neurological Peripheral nerve injury Medicine Chronic Pain medicine.symptom Proto-Oncogene Proteins c-fos Research Article Pain Threshold QH301-705.5 Calcitonin Gene-Related Peptide Science Population Mice Transgenic Calcitonin gene-related peptide Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Spinal Cord Dorsal Horn Physical Stimulation medicine Noxious stimulus Animals education mouse Behavior General Immunology and Microbiology interneurons Animal Neurosciences spinal cord Neural Inhibition Nerve injury Spinal cord Mice Inbred C57BL Disease Models Animal 030104 developmental biology nervous system Disease Models Vesicular Glutamate Transport Protein 1 Cellular Biochemistry and Cell Biology Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| Popis: | Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury. eLife digest The ability to sense pain is critical to our survival. Normally, pain is provoked by intense heat or cold temperatures, strong force or a chemical stimulus, for example, capsaicin, the pain-provoking substance in chili peppers. However, if nerve fibers in the arms or legs are damaged, pain can occur in response to touch or pressure stimuli that are normally painless. This hypersensitivity is called mechanical allodynia. A protein called calcitonin gene-related peptide, or CGRP, has been implicated in mechanical allodynia and other chronic pain conditions, such as migraine. CGRP is found in, and released from, the neurons that receive and transmit pain messages from tissues, such as skin and muscles, to the spinal cord. However, only a few distinct groups of CGRP-expressing neurons have been identified and it is unclear if these nerve cells also contribute to mechanical allodynia. To investigate this, Löken et al. genetically engineered mice so that all nerve cells containing CGRP produced red fluorescent light when illuminated with a laser. This included a previously unexplored group of CGRP-expressing neurons found in a part of the spinal cord that is known to receive information about non-painful stimuli. Using neuroanatomical methods, Löken et al. monitored the activity of these neurons in response to various stimuli, before and after a partial nerve injury. This partial injury was induced via a surgery that cut off a few, but not all, branches of a key leg nerve. The experiments showed that in their normal state, the CGRP-expressing neurons hardly responded to mechanical stimulation. In fact, it was difficult to establish what they normally respond to. However, after a nerve injury, brushing the mice’s skin evoked significant activity in these cells. Moreover, when these CGRP cells were artificially stimulated, the stimulation induced hypersensitivity to mechanical stimuli, even when the mice had no nerve damage. These results suggest that this group of neurons, which are normally suppressed, can become hyperexcitable and contribute to the development of mechanical allodynia. In summary, Löken et al. have identified a group of nerve cells in the spinal cord that process mechanical information and contribute to touch-evoked pain. Future studies will identify the nerve circuits that are targeted by CGRP released from these nerve cells. These circuits represent a new therapeutic target for managing chronic pain conditions related to nerve damage, specifically mechanical allodynia, which is the most common complaint of patients with chronic pain. |
| Databáze: | OpenAIRE |
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