title: Activation of Brainstem Pro-opiomelanocortin Neurons Produces Opioidergic Analgesia, Bradycardia and Bradypnoea.
abstract: Opioids are widely used medicinally as analgesics and abused for hedonic effects, actions that are each complicated by substantial risks such as cardiorespiratory depression. These drugs mimic peptides such as β-endorphin, which has a key role in endogenous analgesia. The β-endorphin in the central nervous system originates from pro-opiomelanocortin (POMC) neurons in the arcuate nucleus and nucleus of the solitary tract (NTS). Relatively little is known about the NTSPOMC neurons but their position within the sensory nucleus of the vagus led us to test the hypothesis that they play a role in modulation of cardiorespiratory and nociceptive control. The NTSPOMC neurons were targeted using viral vectors in a POMC-Cre mouse line to express either opto-genetic (channelrhodopsin-2) or chemo-genetic (Pharmacologically Selective Actuator Modules). Opto-genetic activation of the NTSPOMC neurons in the working heart brainstem preparation (n = 21) evoked a reliable, titratable and time-locked respiratory inhibition (120% increase in inter-breath interval) with a bradycardia (125±26 beats per minute) and augmented respiratory sinus arrhythmia (58% increase). Chemo-genetic activation of NTSPOMC neurons in vivo was anti-nociceptive in the tail flick assay (latency increased by 126±65%, p<0.001; n = 8). All effects of NTSPOMC activation were blocked by systemic naloxone (opioid antagonist) but not by SHU9119 (melanocortin receptor antagonist). The NTSPOMC neurons were found to project to key brainstem structures involved in cardiorespiratory control (nucleus ambiguus and ventral respiratory group) and endogenous analgesia (periaqueductal gray and midline raphe). Thus the NTSPOMC neurons may be capable of tuning behaviour by an opioidergic modulation of nociceptive, respiratory and cardiac control.
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Serena
authors.identifier: http://orcid.org/0000-0001-9548-3145
authors.initials: S
authors.lastname: Cerritelli
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hirschberg
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Rob
authors.initials: R
authors.lastname: Hill
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Nina
authors.initials: N
authors.lastname: Balthasar
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.|Department of Anaesthesia, University Hospitals Bristol, Bristol, BS2 8HW, United Kingdom.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pickering
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001919:Bradycardia / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000075402:Channelrhodopsins; D005260:Female; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012131:Respiratory Insufficiency / Q000378:metabolism*; D017552:Solitary Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000075402:Channelrhodopsins; D009292:Narcotic Antagonists; C103272:SHU 9119; D009270:Naloxone; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones