Dr Raphaelle Quillet
Dr Raphaelle Quillet will be hosting her seminar 'RFRP-3/NPFF1R is a pronociceptive system involved in the development of hyperalgesia induced by opiates and inflammatory pain' here on Thursday 23rd January at 4pm. This will be taking place in the Wolfson Link building, Seminar room 361. All are welcome.
Please see the abstract below.
RFRP-3/NPFF1R is a pronociceptive system involved in the development of hyperalgesia induced by opiates and inflammatory pain
RFRP-3 and NPFF belong to the family of so-called RF-amide. In mammals they are involved in the modulation of several functions including pain and nociception. They target two different G-protein coupled receptor subtypes called NPFF1R and NPFF2R, respectively. However the respective role of these two receptors is unclear and the study of their functions in vivo is severely limited by the lack of highly selective antagonists. In this work, we describe the identification of small compounds that display high affinity and selectivity NPFF1R as well as potent antagonist activity in vitro. We then showed that one of them -RF3286- efficiently and selectively blocks RFRP-3 induced hyperalgesia, indicating that this compound is a useful pharmacological tool to study the in vivo functions of NPFF1R and its endogenous ligand RFRP-3. Pharmacological blockade of NPFF1R with RF3286 prevented the development of pain hypersensitivity and analgesic tolerance induced by chronic administration of morphine revealing that NPFF1R/RFRP-3 system is critically involved in neuroadaptation associated with administration of opiates. These results were further confirmed in NPFF1R knockout animals. Moreover, we observed the expression of NPFF1R and RFRP-3 transcripts by fluorescent in situ hybridization in the dorsal horn of spinal cord, indicating that this receptor/peptide system can modulate nociception in part by spinal mechanism. We further observed that cells expressing NPFF1R transcripts were also MOP positives (50%) and DOP positives (20%), suggesting a direct modulatory role of NPFF1R on the action of opioid. Finally, we observed an increase of NPFF1R positive cells in dorsal horn of spinal cord of CFA-treated animals compared to saline controls suggesting a potential role of this system in inflammatory pain. In agreement with these data, we further showed that pharmacological blockade of NPFF1R with RF3286 can efficiently reverse hyperalgesia induced by CFA injection. Altogether, our data allowed us to identify NPFF1R/RFRP-3 as a pronociceptive anti-opioid system and further suggest that antagonists of this receptor might represent interesting therapeutic tools to limit the development of OIH and analgesic tolerance associated with chronic opioid administration as well as hyperalgesia induced by inflammatory pain.
First published: 7 October 2019