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Title: The role of somatostatin 4 receptors in analgesia
Author: Gorham, Louise
ISNI:       0000 0004 7429 6553
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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Pain is an unpleasant sensory or emotional experience associated with potential or actual tissue damage; presenting a worldwide debilitating problem. Somatostatin is a regulatory cyclic neuropeptide with inhibitory roles in the central nervous system (CNS) via activation of the five somatostatin receptor subtypes belonging to the family of G protein-coupled receptors (GPCRs). Somatostatin is known to exert analgesic effects, which are in part achieved by activation of the somatostatin 4 (sst4) receptor subtype. This research aimed to gain a greater understanding of the role of sst4 receptors in analgesia, with a particular interest in elucidating molecular mechanisms. Using the synthetic sst4 receptor selective agonist, J-2156, the behavioural analgesic profile was established in four analgesic models: the inflammatory Complete Freund ́s Adjuvant (CFA) and monosodium iodacetate (MIA) models; and the neuropathic partial nerve ligation (PNL) and streptozotocin-induced diabetes (STZ) models. Following this mode of action studies were conducted on dissociated dorsal root ganglion (DRG) neurons. J-2156 has a potent analgesic profile. Maximal analgesic effects were seen at 1 mg/kg in all pain models except the MIA model, which required a dose of 10 mg/kg. Analgesia was long-lasting in inflammatory pain models, where significant improvements were present at 24 hours post compound administration. J-2156 modulated the activity of a variety of ion channels within DRG neurons. Activation of sst4 receptors induced a G-protein gated inwardly rectifying potassium channel (GIRK) current and inhibited voltage sensitive calcium channel (Cav), transient receptor potential vanilloid channel (TRPV1) and transient receptor potential ankyrin channel (TRPA1) currents. For all ion channels a concentration-dependent effect was observed, with significant effects first being produced at 10 nM and maximal effects reached at 100 nM. J-2156 caused a significant reduction in paw volume, however this was only seen at doses 10-times that required for analgesia in the CFA model, at 10 mg/kg. This was independent of paw neutrophil and cytokine levels. A significant reduction in inflammatory mediator release from stimulated DRG neurons was observed following incubation with J-2156. The inhibition produced was bell-shaped, where maximal effects were observed at 30 nM. J-2156 modulated the expression of a number of previously characterised pain, inflammatory and immune genes in both DRG neurons and paw tissue, suggesting that the analgesia is in part due to gene normalisation. Overall, this work provides a novel insight into the role of sst4 receptor activation in nociception in chronic pain conditions, indicating contributory molecular mechanisms to the analgesia. From these results it can be concluded that the sst4 receptor presents an appropriate target for novel broad treatment analgesia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available