Mechanisms involved in functional interactions between the Transient Receptor Potential Vanilloid 1 and μ opioid receptor

Vetter, Irina (2007). Mechanisms involved in functional interactions between the Transient Receptor Potential Vanilloid 1 and μ opioid receptor PhD Thesis, School of Pharmacy, University of Queensland.

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Author Vetter, Irina
Thesis Title Mechanisms involved in functional interactions between the Transient Receptor Potential Vanilloid 1 and μ opioid receptor
School, Centre or Institute School of Pharmacy
Institution University of Queensland
Publication date 2007-01-01
Thesis type PhD Thesis
Supervisor Peter J. Cabot
Total pages 442
Language eng
Subjects 11 Medical and Health Sciences
Formatted abstract
Peripheral sensitisation contributes to the development of persistent pain and involves numerous cellular processes. An important receptor in this process is the vanilloid receptor 1 or transient receptor potential vanilloid 1 (TRPV1). TRPV1 is a nociceptive calcium (Ca2+) channel that is activated by capsaicin, the pungent constituent of chilli peppers, as well as protons and heat. TRPV1 is mainly expressed on nociceptive peripheral neurons and appears to be critical in the development of inflammatory and neuropathic hyperalgesia.

Several receptors, including the NGF receptor trkA, the prostaglandin receptor EP1 and the insulin receptor, may functionally interact with TRPV1 to effect sensitisation of TRPV1 in inflammation or neuropathy. Although sensitisation of TRPV1 responses is important, the concept of preventing sensitisation may also be important in modulating signalling through TRPV1. However, few studies have investigated pathways that interact with TRPV1 to prevent sensitisation.

As a prototypical G-protein coupled receptor that produces analgesic effects upon activation, one such potential modulator is the μ opioid receptor or MOP. This thesis thus aims to provide insight into the pathways involved in putative functional interactions between TRPV1 and MOP.

This thesis describes confirmation of co-expression of TRPV1 and MOP in a substantial proportion of TRPV1-expressing cultured adult rat dorsal root ganglion neurons using immunofluorescence studies, thus forming the basis for a functional interaction of the nociceptive TRPV1 and antinociceptive MOP in neuronal cells. However, owing to the heterogeneity of TRPV1 and MOP expression in neuronal subsets, a human embryonic kidney 293 (HEK) cell line stably expressing TRPV1 and MOP was generated to enable study of the pathways and mechanisms involved in putative functional interactions between the receptors.

The effect of the MOP agonist morphine on TRPV1 function was assessed by measurement of TRPV1-mediated Ca2+ responses in Fluo-3-loaded cells using a fluorescent microplate reader. Although morphine did not affect unpotentiated TRPV1 responses, based on the observation that opioids are particularly effective in inflammation, but ineffective in neuropathies, the ability of morphine to inhibit TRPV1 responses sensitised by cAMP-dependent PKA as well as PKC and insulin was assessed. Pre-treatment with morphine inhibited TRPV1-mediated capsaicin responses potentiated by the adenylate cyclase activator forskolin. However, TRPV1-mediated Ca2+ responses potentiated by the direct PKA activator 8-Br-cAMP, the PKC activator Phorbol-12- myristate-13-acetate and ethanol were not modulated by morphine. The results presented here indicate that the MOP agonist morphine acts via inhibition of adenylate cyclase to inhibit PKA-potentiated TRPV1 responses. In light of increased PKA activity in inflammation, MOP-mediated inhibition of TRPV1 responses sensitised by cAMPdependent PKA may be of particular relevance to inflammatory hyperalgesia.        ................................
Keyword TRP channels
Opioids receptors

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Created: Fri, 24 Oct 2008, 22:43:42 EST