Pro-opiomelanocortin (POMC) is a precursor polypeptide that can be differentially cleaved into various biologically active peptides that have diverse effects. POMC is produced in neurones that are located in two distinct regions of the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract in the medulla (NTS). POMC neurones in the ARC have been well described in terms of their anatomical distribution and functional role, however NTS POMC neurones have not. The NTS is a major structure involved in cardiorespiratory regulation and is also linked to nociceptive processing, where NTS stimulation is antinociceptive. ~-endorphin, a cleavage peptide of POMe, is an opioid known to produce potent and lasting analgesia and can also affect cardiorespiratory function. NTS POMC neurones could provide a source of ~endorphin release within the brainstem. This project will test the hypothesis that NTS POMC neurones are involved in cardiorespiratory and nociceptive processing, via release of ~-endorphin. This project has employed viral vector-mediated strategies in POMC-Cre-ROSAGFP mice in order to: (i) opto-activate NTS POMC-Cre neurones and examine effects on cardiorespiratory control in the working heart-brainstem preparation; (ii) study the anatomical projections of NTS POMC-Cre neurones throughout the brain; and (iii) pharmacologically activate NTS POMC-Cre neurones in awake, behaving mice to examine influence on respiratory function, food intake and nociception. Opto-activation of NTS POMC-Cre neurones elicited profound cardiorespiratory responses, including a bradycardia, transient apnoea and increased respiratory sinus arrhythmia. These responses were attenuated by systemic naloxone. The bradycardias were mimicked by DAMGO microinjection into the nucleus ambiguus (NA), but not NTS. NTS POMC-Cre neuronal fibres projected to specific target sites within the brainstem, including the NA, ventral respiratory column, dorsal motor nucleus of the vagus, raphe obscurus nucleus, lateral reticular nucleus and hypoglossal nucleus. Pharmaco-activation of NTS POMCCre neurones resulted in increased tail-flick latencies, which were abolished by systemic naloxone. Taken together these results show that activation of NTS POMC-Cre neurones can produce antinociceptive effects, exert a potent facilitatory influence on cardiac vagal outflow and can inhibit the respiratory network. These responses are likely to be mediated by the opioid peptide ~-endorphin. The projections of POMC-Cre neuronal fibres outside of the NTS suggest that they form an output path to other CNS sites. These results suggest that NTS POMC-Cre neurones may have an opioid-mediated role in autonomic modulation and somatic nociception.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:680139 |
| Date | January 2014 |
| Creators | Cerritelli, Serena |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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