Nociceptin/orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons

被引:18
作者
Anand, Praveen [1 ]
Yiangou, Yiangos [1 ]
Anand, Uma [1 ]
Mukerji, Gaurav [1 ]
Sinisi, Marco [2 ]
Fox, Michael [2 ]
McQuillan, Anthony [2 ]
Quick, Tom [2 ]
Korchev, Yuri E. [1 ]
Hein, Peter [3 ]
机构
[1] Imperial Coll London, Hammersmith Hosp, Dept Med, London, England
[2] Royal Natl Orthopaed Hosp, Peripheral Nerve Injury Unit, Stanmore, Middx, England
[3] Grunenthal GmbH, Grunenthal Innovat Translat Sci & Strategy, Aachen, Germany
关键词
NOP receptor; Nociceptin/orphanin FQ; Pain; Bladder; NEUROGENIC DETRUSOR OVERACTIVITY; ROOT GANGLION NEURONS; RAT SENSORY NEURONS; AGONIST SCH 221510; ORL1; RECEPTOR; ORPHANIN-FQ; CAPSAICIN RESPONSES; INFLAMMATORY PAIN; MEDIATED INHIBITION; MICTURITION REFLEX;
D O I
10.1097/j.pain.0000000000000597
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
The nociceptin/orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand nociceptin/orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry and assessed functional effects of NOP and mu-opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder suburothelium revealed a remarkable several-fold increase in detrusor overactivity (P<0.0001) and painful bladder syndrome patient specimens (P - 0.0014) compared with controls. In postmortem control human DRG, 75% to 80% of small/medium neurons (<= 50 mu m diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP immunoreactivity was significantly decreased in injured peripheral nerves (P = 0.0004), and also in painful neuromas (P = 0.025). Calcium-imaging studies in cultured rat DRGneurons demonstrated dose-dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (P < 0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than mu-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials.
引用
收藏
页码:1960 / 1969
页数:10
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